Links

Images

Classifications

C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms

C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings

C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07D—HETEROCYCLIC COMPOUNDS

C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom

C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00

C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings

C07D487/08—Bridged systems

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07D—HETEROCYCLIC COMPOUNDS

C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms

C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings

C07D495/04—Ortho-condensed systems

Abstract

Mono-flourinated and di-fluorinated benzothiepine apical sodium co-dependent bile acid transport (ASBT) inhibitors are disclosed together with methods of making the same, methods of using the same to treat hyperlipidemic conditions as well as pharmaceutical compositions containing the same compounds.

Description

This is a non-provisional application which claims the benefit of priority of provisional Application No. 60/330,892, filed Nov. 2, 2001, the subject matter of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to compounds, pharmaceutical compositions, and methods for treating high blood cholesterol levels in a subject. More particularly, the present invention relates to novel mono-fluorinated or di-fluorinated benzothiepine compounds that are useful as apical sodium co-dependent bile acid transport (ASBT) inhibitors, pharmaceutical compositions containing the same, methods for making the same and methods for treating hyperlipidemic conditions.

DESCRIPTION OF THE RELATED ART

The major metabolic fate of cholesterol in the human body is in the hepatic synthesis of bile acids. Bile acids are both passively and actively reabsorbed from the small intestine and recycled via the enterohepatic circulation to conserve the total pool of bile acids. Dietschy, “Mechanisms for the intestinal absorption of bile acids”, J. Lipid Res., 9:297-309 (1968). Bile acids undergo passive absorption in the proximal small intestine and active transport in the terminal ileum. Love et al., “New insights into bile acid transport”, Curr. Opin. Lipidol., 9 (3):225-229 (1998). Ileal active transport accounts for the majority of intestinal bile acid uptake and is the exclusive route for taurine-conjugated bile acids. Id. Ileal active transport is mediated by the apical sodium co-dependent bile acid transporter (“ASBT”, also known as the ileal bile acid transporter or “IBAT”) localized to the distal one-third of the ileum. Craddock et al., “Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter”, Am. J. Physiol., 274 (Gastrointest. Liver Physiol. 37):G157-G169 (1998).

An equilibrium generally exists between hepatic cholesterol and the bile acid pool. Interruption of the enterohepatic recirculation of bile acids (e.g., the binding of intestinal bile acids to a sequestering resin such as cholestyramine; the surgical removal of the ileum to physically eliminate ileal ASBT; or the specific inhibition of ileal ASBT) results in a decrease in the liver bile acid pool and stimulates increased hepatic synthesis of bile acids from cholesterol (i.e., an upregulation of cholesterol-7∀-hydroxylase activity), eventually depleting the liver's pool of esterified cholesterol. In order to maintain liver cholesterol levels necessary to support bile acid synthesis, the de novo synthesis of cholesterol increases in the hepatocytes (i.e., an upregulation of 3-hydroxy-3-methylglutaryl coenzyme-A reductase activity) and also increases the uptake of serum cholesterol by upregulating the number of cell surface low density lipoprotein cholesterol receptors (“LDL receptors”). The number of hepatic LDL receptors directly impacts serum low density lipoprotein (“LDL”) cholesterol levels, with an increase in the number of LDL receptors resulting in a decrease in serum cholesterol. The net result, therefore, is that serum LDL cholesterol levels decrease when intestinal bile acid reabsorption is reduced.

A class of antihyperlipidemic agents that operates by inhibiting bile acid reabsorption in the ileum recently has been identified. Examples of this class of agents include the substituted benzothiepines disclosed in U.S. Pat. No. 5,994,391. PCT Patent Application No. WO99/35135 discloses additional substituted benzothiazepine compounds for use as ASBT inhibitors. By way of further example, PCT Patent Application No. WO94/24087 discloses a group of substituted naphthalene compounds for use as ABST inhibitors. The United States Food and Drug Administration, however, has not approved any ASBT inhibitor for use as an antihyperlipidemic agent at this time.

Numerous antihyperlipidemic agents having other modes of action also have been disclosed in the literature as useful for the treatment of hyperlipidemic conditions and disorders. These agents include, for example, commercially available drugs such as nicotinic acid, bile acid sequestrants including cholestyramine and colestipol, 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (“HMG Co-A reductase inhibitors”), probucol, and fibric acid derivatives including gemfibrozil and clofibrate.

The class of antihyperlipidemic agents known as HMG Co-A reductase inhibitors operates by inhibiting the hepatic enzyme 3-hydroxy-3-methylglutaryl coenzyme-A reductase (“HMG Co-A reductase”). Direct inhibition of HMG Co-A reductase by the monotherapeutic administration of HMG Co-A reductase inhibitors such as pravastatin has been shown to be a clinically effective method of lowering serum LDL cholesterol. Sacks et al., “The Effect of Pravastatin on Coronary Events after Myocardial Infarction in Patients with Average Cholesterol Levels”, New England Journal of Medicine, 335(14):1001-9 (1996). Monotherapeutic treatment with pravastatin may lead to upregulation of cell surface LDL receptors as a mechanism to provide cholesterol to the liver in support of bile acid synthesis. Fujioka et al., “The Mechanism of Comparable Serum Cholesterol Lowering Effects of Pravastatin Sodium, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Inhibitor, between Once- and Twice-Daily Treatment Regimens in Beagle Dogs and Rabbits”, Jpn. J. Pharmacol., Vol. 70, pp. 329-335 (1996).

The administration of an ASBT inhibitor in combination with an HMG Co-A reductase inhibitor is generally disclosed in PCT Application WO98/40375.

The treatment of hypercholesterolemia with an HMG Co-A reductase inhibitor in combination with a bile acid sequestering resin also has been reported in the literature. The administration of the HMG Co-A reductase inhibitor lovastatin in combination with the bile acid sequestering resin colestipol is disclosed in Vega et al., “Treatment of Primary Moderate Hypercholesterolemia With Lovastatin (Mevinolin) and Colestipol”, JAMA, Vol. 257(1), pp. 33-38 (1987). The administration of the HMG Co-A reductase inhibitor pravastatin in combination with the bile acid sequestering resin cholestyramine is disclosed in Pan et al., “Pharmacokinetics and pharmacodynamics of pravastatin alone and with cholestyramine in hypercholesterolemia”, Clin. Pharmacol. Ther., Vol. 48, No. 2, pp. 201-207 (August 1990).

The treatment of hypercholesterolemia with other selected combination regimens also has been reported in the literature. Ginsberg, “Update on the Treatment of Hypercholesterolemia, with a Focus on HMG Co-A Reductase Inhibitors and Combination Regimens”, Clin. Cardiol., Vol. 18(6), pp. 307-315 (June 1995), reports that, for resistant cases of hypercholesterolemia, therapy combining an HMG Co-A reductase inhibitor with either a bile acid sequestering resin, niacin or a fibric acid derivative generally is effective and well tolerated. Pasternak et al., “Effect of Combination Therapy with Lipid-Reducing Drugs in Patients with Coronary Heart Disease and ‘Normal’ Cholesterol Levels”, Annals of Internal Medicine, Vol. 125, No. 7, pp. 529-540 (Oct. 1, 1996) reports that treatment with either a combination of the HMG Co-A reductase inhibitor pravastatin and nicotinic acid or a combination of pravastatin and the fibric acid derivative gemfibrazol can be effective in lowering LDL cholesterol levels.

It is desirable to provide novel ASBT inhibitors that exhibit improved efficacy, improved potency, and/or reduced dosing requirements for the active compounds relative to the specific combination regimens previously disclosed in the published literature.

SUMMARY OF THE INVENTION

According to one embodiment, the invention comprises novel fluorinated benzothiepine compounds corresponding to Formulas I-1 to I-24 (see the Detailed Description, infra) that are effective agents for the treatment of one or more hyperlipidemic condition(s).

According to another embodiment, the invention comprises pharmaceutical compositions comprising one or more of the novel fluorinated benzothiepine compounds corresponding to Formulas I-1 to I-24 that are suitable for use in treating one or more hyperlipidemic condition(s).

According to yet another embodiment, the invention comprises a method for treating one or more hyperlipidemic condition(s) comprising administering to a subject a therapeutically effective amount of one or more of the novel fluorinated benzothiepine compounds corresponding to Formulas I-1 to I-24.

According to still another embodiment, the invention comprises methods for making the novel benzothiepine compounds corresponding to Formulas I-1 to I-24. Other aspects of the invention will be apparent to those of ordinary skill in view of the present description provided below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

According to one embodiment, the invention comprises novel mono-fluorinated and di-fluorinated benzothiepene compounds defined by Formulas I-1 to I-8:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof

wherein j is 0, 1 or 2; m is 0, 1, 2, 3 or 4;

wherein R2A and R2B are independently selected from the group consisting of hydrogen and hydrocarbyl;

wherein when R5 is said cycloalkyl, aryl or heterocyclyl, said cycloalkyl, aryl or heterocyclyl are optionally substituted with —NH—X—R or —O—X—R;

wherein X is selected from the group consisting of —(C═O)s-alkyl-; —(C═O)s-alkyl-NH—; —(C═O)s-alkyl-O—; —(C═O)s-alkyl-(C═O)t; and a covalent bond, wherein s and t are independently 0 or 1;

wherein R is selected from the group consisting of monosaccharides, disaccharides, and polysaccharides, wherein said monosaccharides, disaccharides, and polysaccharides are optionally protected with one or more sugar protecting groups;

wherein, in each instance, said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein, in each instance, said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus and combinations thereof.

In one embodiment, aryl-R5 is phenyl substituted with —N(H)—X—R33 or —O—X—R33 wherein X is selected from the group consisting of:

—(C═O)s-alkyl-; —(C═O)s-alkyl-NH—; —(C═O)s-alkyl-O—; —(C═O)s-alkyl-C═O)t; and a covalent bond; wherein R33 is selected from selected from the group consisting of monosaccharides,disaccharides, and polysaccharides; and s and t are independently 0 or 1.

In one embodiment, aryl-R5 is phenyl substituted at the para-position with —N(H)—X—R33 or —O—X—R33 wherein X is selected from the group consisting of:

—(C═O)s-alkyl-; —(C═O)s-alkyl-NH—; —(C═O)s-alkyl-O—; —(C═O)s-alkyl-C═O)t; and a covalent bond; and wherein R33 is selected from selected from the group consisting of monosaccharides, disaccharides, and polysaccharides; and s and t are independently 0 or 1.

In another embodiment, aryl-R5 is phenyl substituted at the meta-position with —N(H)—X—R33 or —O—X—R33 wherein X is selected from the group consisting of:

—(C═O)s-alkyl-; —(C═O)s-alkyl-NH—; —(C═O)s-alkyl-O—; —(C═O)s-alkyl-C═O)t; and a covalent bond; and R33 is selected from selected from the group consisting of monosaccharides,disaccharides, and polysaccharides; and s and t are independently 0 or 1.

In another embodiment, aryl-R5 is phenyl substituted with a radical selected from the group consisting of members (1)-(24), (25)-(48), or (49)-(70), of Table 1 below.

Yet, even further, R5A and R5B may independently have the formula (II):

wherein t and R5 are as previously described.

Furthermore, one or more R6 radicals are in the 6-, 7-, 8- and/or 9-position of the benzo ring of formulas I-1 to I-24 described herein. Preferably, R6 is in the 7-, 8- and/or 9-position of the benzo ring of formulas I-1 to I-24. More preferably, R6 is in the 7- and/or 8-position of the benzo ring of formulas I-1 to I-24. Furthermore, R6 is independently selected from the group consisting of:

wherein R7, R8, R9, R10, R11, R12, R13, R14, R15 and A− are as previously defined and R16 and R17 are independently selected from the group consisting of hydrogen and alkyl, and optionally R13=R14=methyl;

wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR9, N+R9R10A−, S, SO, SO2, S+R9A−, PR9, P+R9R10A−, or P(O)R9;

(c) polyether, OR13, NR13R14 and N+R9R11R12A−;

(d) polyether, OR13 and NR13R14.

According to another embodiment, the class of ASBT inhibitor compounds are as previously defined by Formulas I-1 to I-8 except that:

j is 2;

R2A and R2B are hydrogen;

wherein R3A and R3B are independently selected from the group consisting of hydrogen and alkyl; and

wherein R5A and R5B are independently selected from the group consisting of hydrogen and phenyl optionally substituted at the meta or para position with R5 selected from the group consisting of members (1)-(70) denoted in Table 1 below. It is noted that when R5 is a bridging linkage, dimeric or polymeric compounds of the type {-benzothiepene-bridge-benzothiepene-} are formed wherein the benzothiepene is selected from the group consisting of Formulas I-1 to I-24 and exemplary bridging R5 groups include, but are not limited to, (7), (17) and (24) in Table 1 below.

TABLE 1

R5

(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(15a)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47)

(48)

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

(59)

(60)

(61)

(62)

(63)

(64)

(65)

(66)

(67)

(68)

(69) and

(70)

Also, in tails (1)-(70) the specified anion may be replaced by another pharmaceutically acceptable anion (e.g., A− which anion is as previously described). Optionally, R5 may be selected from the following: (1)-(24), (25)-(48) or (49)-(70) from Table 1. Further, R5 may be acidic or contain a quarternary ammonium nitrogen. Even further, R5 may be selected from the following: (1)-(5), (6)-(10), (11)-(15), (16)-(20), (21)-(25), (26)-(30), (31)-(35), (36)-(40), (41)-(45), (46)-(50), (51)-(55), (56)-(60), (61)-(65), (66)-(70), or combinations thereof from Table 1.

Other exemplary embodiments of ASBT inhibitors of the present invention are represented by Formulas I-9 to I-16 below.

herein R3A and R3B are independently selected from hydrogen and alkyl, wherein R6 is the same as previously defined, and wherein R5 is selected from the members (1)-(70) of Table 1 above. Note that while R5 is described as being attached to the para-position of the phenyl ring, R5 may be attached to either the ortho or the meta position of the subject phenyl ring described above (e.g., where appropriate, in any of Formulas I-9 to I-16 above and in any of Formulas I-17 to I-24 depicted below.). Preferably, the R5 substituent is at the meta- or the para-position of the C5-phenyl group.

Additional exemplary embodiments of ASBT inhibitors of the present invention are represented by formulas I-17 to I-24 below:

The novel fluorinated benzothiepine compounds of the present invention are safe and effective anti-hyperlipidemic agents. These compounds generally exhibit at least one desirable characteristic which includes, but is not limited to: (a) improved potency, (b) improved solubility profile, (c) improved compatibility with conventional routes of oral administration, (d) improved safety profile, and (e) elimination of a chiral center at the 4-position ring carbon in the case of the novel di-fluorinated benzothiepenes of the present invention.

The compounds of the present invention are useful for, but not limited to, the treatment of one or more hyperlipidemic condition(s) including the prophylactic treatment of hyperlipidemia in a subject. The methods, compounds, pharmaceutical compositions and kits of the present invention also are useful for the prophylaxis and/or treatment of gallstones. Besides being useful for human treatment, the above-described compounds (e.g., I-1 to I-24) also are useful for veterinary treatment of companion animals (e.g., horses, dogs, cats, etc.), exotic animals and farm animals, including mammals, rodents, and the like. Even though the invention is described in terms of human biology, it will be understood by those of ordinary skill that the present invention is applicable to other mammals, as well.

The above-noted ASBT inhibitors of the present invention may be made according to the exemplary chemical Schemes 1 and 2 below:

As indicated in Scheme 1, the aldehyde S1-1 is reacted with formaldehyde or an aldehyde and sodium hydroxide to yield the compound S1-2 which is converted to the mesylate S1-3 with methanesulfonyl chloride or other suitable leaving group and triethylamine as an exemplary solvent. See, for example, Chem. Ber. 98, 728-734 (1965). Reaction of the mesylate S1-3 with the thiophenol S1-4 in triethylamine yields the keto-aldehyde S1-5, which is prepared according to the procedure indicated in WO 93/16055. The keto-aldehyde S1-5 is then cyclized with a suitable cyclicizing agent such as Zn/TiCl3 in refluxing ethylene glycol dimethyl ether (DME) to yield a racemic mixture of the ketone S1-7 and S1-8 (when R3A≠R3B) together with compound S1-6. Treatment of S1-7 and S1-8 with excess (e.g., 3 equivalents) of m-chloro-perbenzoic acid (MCPBA) yields the a sulfone epoxide (not shown) which, in turn, upon hydrogenation with palladium on carbon (H2/Pd—C) as catalyst yields a racemic mixture of S1-7a and S1-8a (when R3A≠R3B) and another racemic mixture of S1-6a and S1-6b (when R3A≠R3B). It is noted that optically active compounds of the present invention can be prepared by using optically active starting materials of compound S1-2 or by resolution of compounds S1-7a and S1-8a. Resolution of compounds S1-7a and S1-8a can be accomplished with optical resolution agents well known in the art and described in J. Org. Chem., 39 (26), 3904-3906 (1974), J. Org. Chem., 42 (16), 2781-2782 (1977) and J. Org. Chem., 44 (26), 4891-4896 (1979).

Alcohols S1-7a and/or S1-8a can be converted to the mono-fluorinated compounds S1-7b and S1-8b by treatment with dimethylaminosulfur trifluoride (Et2NSF32) in accordance with the procedure outlined in J. Org. Chem., 40(5), 574-578 (1975) with retention of stereochemistry. In particular, the alcohol S1-7a and/or S1-8a is/are added to a solution of (Et2NSF32) in an inert solvent cooled to −50 to −78° C. The reaction mixture is then warmed to room temperature (or higher). Typically, an initial exothermic reaction may occur during the warm-up period. On occasion, a second exothermic reaction may also occur during the warm-up period. Lower boiling fluorides are distilled out of the reaction mixture at reduced pressure to yield compounds S1-7b and/OR S1-8b. For the higher boiling fluorides, the reaction mixture should be mixed with water, the organic layer separated and dried, and any solvent should be removed from the separated organic layer by distillation. The product fluoride compounds can then be further purified by recyrstallization, or column chromatography.

To obtain the diflourinated compounds 7d and/or 8d, compounds S1-7a and/or S1-8a should first be converted to the ketones S1-7c and/or S1-8c by treatment with oxalyl chloride, triethanolamine (TEA) and dimethyl sulfoxide (DMSO) as indicated in J. Org. Chem., 65 (9), 2711-2715 (2000). Thereafter, ketones S1-7c and/or S1-8c can be converted to the difluorinated compounds S1-7d and/or S1-8d by the same procedure previously described for the conversion of S1-7a and S1-8a to S1-7b and S1-8b outlined in J. Org. Chem. 40(5), 574-578 (1975).

Also, optically active compounds S1-7d and S1-8d can be obtained by using optically active starting materials of compounds S1-2 or S1-3 or by using previously described optical resolving agents to separate optically active compounds S1-7a and S1-8a from each other. Thereafter, separated compounds S1-7a and S1-8a should be converted to S1-7c and S1-8c followed by conversion to S1-7d and S1-8d, respectively, as indicated above.

In Scheme 2, compound S2-30 is converted to compound S2-32 with triethylsilane and trifluoromethane sulfonic acid. Reaction of S2-32 with lithium sulfide followed by reacting the resulting sulfide with the mesylate S2-33 gives the sulfide S2-34. Oxidation of S2-34 with 2 equivalents of MCPBA, followed by reduction with H2—Pd/C, protection of the resulting hydroxylamine with di-t-butyldicarbonate, cyclization with potassium t-butoxide, removal of the t-butoxycarbonyl protecting groups (and acid workup) and hydrogenation with Pd/C—H2 at 100 psi and 50° C. yields compounds S2-36, S2-38, S2-40 and S2-42 wherein, for example, R6=—NH2 and m=1 (integer). In Scheme 2, compounds S2-36, S2-38, S2-40 and S2-42 are made using chiral starting materials of compound 33 or by resolving the chiral compounds S2-36, S2-38, S2-40 and S2-42 using the previously noted optical resolution agents. Further, in Scheme 2, Y typically is OMe. However, Y may be another alkoxy, or a halogen (F, Cl, Br, and I).

Exemplary conversion of 36, 38, 40 and 42 (e.g., wherein R6=—NH2 and m=1 and Y=OMe) into 44, 46, 48 and 50 is accomplished according to the procedure outlined in Step 9 of Example 1401, infra. In particular, the methoxy compounds S2-36, S2-38, S2-40 and/or S2-42 (e.g., Y=OMe) and CH3Cl are placed in a flask purged with N2. The reaction mixture is then cooled to −78° C. and boron tribromide (BBr3) is added. The mixture is allowed to warm to room temperature. After about 4 hours, the reaction mixture is cooled to 0° C. and then quenched with 10% K2CO3. Thereafter (about 10 min. later), the layers are separated and the aqueous layers extracted twice with ethyl ether. The CHCl3 and ether extracts are combined, washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated in vacuo to yield the products S2-44, S2-46, S2-48 and /or S2-50.

Compounds S2-44, S2-46, S2-48 and S2-50 are then converted to compounds S2-52, S2-54, S2-56 and S2-58 (wherein R5 is a moiety selected from members (1)-(70) depicted in Table 1 above) according to the procedures for adding the same groups described and outlined in the Examples, infra.

After formation of compounds S2-52, S2-54, S2-56 and/or S2-58 (either formed with chiral starting materials or resolved using optical resolving agents), these compounds are subjected to the same mono-fluorinating procedures previously described and outlined in Scheme 1 for the conversion of S1-7a and Si-8a to S1-7b and S1-8b. By carrying out such steps, the corresponding mono-fluorinated compounds of S2-52, S2-54, S2-56 and/or S2-58 are formed, wherein a single C—F bond is formed at the C-4 carbon of the benzothiepine ring, exemplarily depicted in Formulas I-2 to I-8, Formulas I-11 to I-16, Formulas I-19 to I-20, and Formulas I-23 to I-24.

Similarly, the corresponding di-fluorinated compounds of the hydroxy compounds S2-52, S2-54, S2-56 and/or S2-58 are made by subjecting compounds S2-52, S2-54, S2-56 and/or S2-58 to the same di-fluorinating procedures previously described and outlined in Scheme 1 for the conversion of S1-7a and S1-8a to S1-7d and S1-8d. By so doing, the corresponding di-fluorinated compounds of the hydroxy compounds S2-52, S2-54, S2-56 and/or S2-58 are formed. Exemplary difluorinated compounds are depicted in Formulas I-1, I-9, I-10, I-17, and I-22.

Additional Schemes for forming compounds S3-11c and S3-11d analogous to compounds S1-7a and S1-8a are provided in Schemes 3-5 below. Scheme 6 below outlines the procedures for forming other compounds S6-15c and S6-15d analogous to compounds S3-11c and S3-11d, where the stereochemistry at the C-3 carbon is varied when R3A≠R3B. Once formed, compounds S3-11c, S3-11d, S6-15c and S6-15d are subjected to the procedures previously described and outlined in Scheme 2 for the attachment of R5 groups and then subjected to the procedures previously described and outlined in Scheme 1 for formation of the analogous mono-fluorinated and di-fluorinated compounds having the appropriate R5 groups attached off of the phenyl ring attached to the C-5 carbon as depicted or indicated in connection with one or more of Formulas I-1 to I-24. Finally, Scheme 7 below outlines the procedure for forming compound S7-9 utilized in Scheme 3. Schemes 3-7 are as follows:

In Scheme 3, compound S1-3 is formed according to the same procedure outlined in Scheme 1. Thereafter, compound S1-3 is reacted with thiophenol S7-9 (e.g., made according to Scheme 7, infra) to yield the sulfide-aldehyde S3-10. Oxidation of S3-10 with 2 equivalents of MCPBA and then cyclization with potassium t-butoxide yields compounds S3-11c and S3-11d. As noted with Scheme 1, either chiral starting materials (such as chiral starting compounds corresponding to those of S1-2) or optical resolving agents may be used to form compounds S3-11c and/or S3-11d.

In Scheme 4, compound 8c is reduced with NaBH4 to yield compounds S4-11a and/or S4-11b (made with chiral starting materials or optical resolving agents). Both S4-11a and S4-11b depict the R5A group and the OH group on opposite sides. Compounds S4-11a and S4-11b can be converted to compounds S3-11c and S3-11d, respectively, by treating the former compounds (S4-11a and/or S4-11b) in methylene chloride with 40-50% sodium hydroxide in the presence of a phase transfer catalyst (PTC). The transformation of S4-11a and S4-11b to S3-11c and S3-11d, respectively, can also be carried out with potassium t-butoxide in tetahydrofuran (THF).

In Scheme 5, compound S1-5 is made according to the procedures described and outlined in Scheme 1. Compound S1-5 is oxidized with 2 equivalents of MCPBA and then treated with H2—Pd/C when R6=NO2, and protect with (BOC)2O to yield compound S4-5a. Compound S4-5a, in turn, is cyclized with potassium t-butoxide to yield compounds S3-11c, S3-11d, S6-15c and/or S6-15d (as earlier noted, S3-11c, S3-11d, S6-15c, and/or S6-15d are formed using chiral starting materials or with optical resolving agents).

In Scheme 6, compound S1-7c (formed according to Scheme 1) is reduced with sodium borohydride to give compounds S6-15a and/or S6-15b. Note that compounds S6-15a and S6-15b are formed by utilizing chiral starting materials or by using optical resolving agents. Thereafter, compounds S6-15a and S6-15b can be converted to compounds S6-15c and S6-15d, respectively, by reaction in methylene chloride with 40-50% sodium hydroxide in the presence of a phase transfer agent (PTC) as previously described in connection with Scheme 4.

Scheme 7 outlines an exemplary process for forming compound S7-9 used in Scheme 1. In particular, compound S7-17 is alkylated with an arylmethyl chloride in a nonpolar solvent according to J. Chem. Soc., part 2, 2431-2432 (1958) which gives the ortho-substituted phenol S7-18. Phenol S7-18 is converted to the thiophenol S7-9 via thiocarbamate S7-20 by the procedure described in J. Org. Chem., 31, 3980-3984 (1966). The phenol S7-18 is first reacted with dimethyl thiocarbamoyl chloride and triethylamine to give the thiocarbamate 20 which is chemically rearranged at 200-300° C., and then the rearranged product is hydrolyzed with sodium hydroxide to yield the thiphenol S7-9. Alternatively, thiphenol S7-9 can also be obtained from an analogous 2-acylphenol (i.e., analogous to S7-18 wherein the carbon to which R5A is attached has a carbonyl oxygen attached to it as well—not shown) via the thiocarbamate intermediate S7-20 using ClC(S)N(CH3)2 as used before to convert S7-18 to S7-20.

two R6 groups attached to adjacent carbon atoms (e.g., adjacent carbon atoms on the benzo ring) together with the carbon atoms to which they are attached form a C4-C12 mono- or bi-cyclic carbocyclic or heterocyclic ring; a mono- or bi-cyclic carbocyclic or heterocyclic ring; or a mono- or bi-cyclic carbocyclic or heterocyclic ring;

(h) wherein R11 and R12 are independently selected from the group consisting of hydrogen; —CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; heterocyclylalkyl; carboxyalkyl; alkoxyalkyl; carboalkoxyalkyl; cycloalkyl; cycloalkenyl; haloalkyl; hydroxyalkyl; cyanoalkyl; —OR9; —NR9R10; —SR9; —S(O)R9; —SO2R9; —SO3R9; —CO2R9; and —CONR9R10; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and

(i) wherein R13, R14, and R15 are independently selected from the group consisting of hydrogen; alkyl; haloalkyl; cycloalkyl; polyalkyl; alkenyl; alkynyl; aryl; heterocyclyl; quaternary heterocyclyl; arylalkyl; heterocyclylalkyl; quaternary heterocyclylalkyl; alkylarylalkyl; alkylheterocyclylalkyl; alkylammoniumalkyl; aminoalkyl; aminocarbonylalkyl; alkylaminocarbonylalkyl; carboxyalkylaminocabonylalkyl; and polyether, or R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or

wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and

According to another embodiment, the invention includes compounds of formulas I-1 to I-24 having the following substituents:

(a1) R2A and R2B are independently selected from the group consisting of hydrogen and alkyl;

(b1) R3A and R3B are independently selected from the group consisting of hydrogen; alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl; or

R3A and R3B taken together with the carbon to which they are attached form C3-C7 cycloalkyl or C3-C7 cycloalkenyl;

wherein the R3A and R3B alkyl; cycloalkyl; alkenyl; alkynyl; arylalkyl; alkoxyalkyl; alkoxyalkenyl; alkoxyalkynyl; alkylaryl; and (polyalkyl)aryl radicals optionally may be substituted with one or more radicals selected from the group consisting of —CN; halogen; oxo; —OR9; —NR9R10; —NR9R10RWA−; —SR9; —S+R9R10A−; —PR9R10; —P+R9R10RWA−; —S(O)R9; —SO2R9; —SO3R9; —CO2R9; and —CONR9R10; and

wherein the one or more R6 radicals comprising carbon optionally may independently have one or more carbons replaced by —O—; —NR13—; —N+R13R14A−—; —S—; —SO—; —SO2—; —S+R13A−—; —PR13—; —P(O)R13—; —PR13—; —P+R13R14A−—; phenylene; amino acid; peptide; polypeptide; carbohydrate; polyether; or polyalkyl; wherein said phenylene; amino acid; peptide; polypeptide; carbohydrate; and polyalkyl optionally may have one or more carbons replaced by —O—; —NR9—; —N+R9R10A−—; —S—; —SO—; —SO2—; —S+R9A−—; —PR9—; —P+R9R10A−—; or —P(O)R9—; or

two R6 groups attached to adjacent carbon atoms (e.g., adjacent carbon atoms on the benzo ring) together with the carbon atoms to which they are attached form a C4-C10 mono- or bi-cyclic carbocyclic or heterocyclic ring;

R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or

wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and

two R6 groups attached to adjacent carbon atoms (e.g., adjacent carbon atoms on the benzo ring) together with the carbon atoms to which they are attached form a C4-C10 mono or bi-cyclic carbocyclic or heterocyclic ring;

(h2) wherein R11 and R12 are independently selected from the group consisting of hydrogen; —CN; halogen; oxo; (C1-C10)alkyl; (C2-C10)alkenyl; (C2-C10)alkynyl; aryl; heterocyclyl; aryl(C1-C10)alkyl; carboxy(C1-C10)alkyl; carbo(C1-C10)alkoxy(C1-C10)alkyl; (C3-C10)cycloalkyl; cyano(C1-C10)alkyl; —OR9; —NR9R10; —SR9; —S(O)R9; —SO2R9; —SO3R9; —CO2R9; and —CONR9R10; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring;

wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or

wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and

(l2) wherein R19 and R20 are independently selected from the group consisting of hydrogen and (C1-C10)alkyl; and

(m2) same as (m1) above;

(n2) provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl;

(o2) provided that heterocyclyl is selected from the group consisting of optionally substituted heterocyclyl comprising a 4 to 10 membered ring and comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus.

According to another embodiment, the substituents on the compounds of formulas I-1 to I-24 are as follows:

(a3) R2A and R2B are independently selected from the group consisting of hydrogen and (C1-C10)alkyl;

(b3) R3A and R3B are independently selected from the group consisting of hydrogen and (C1-C10)alkyl; or

R3A and R3B taken together with the carbon to which they are attached form (C3-C7)cycloalkyl;

(c3) R4A and R4B are independently selected from the group consisting of hydrogen and —OR9;

(d3) R5A is selected from phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from the group consisting of R5 halogen; hydroxy, —NO2; (C1-C10)alkyl; halo(C1-C10)alkyl;

(f3) one or more R6 (wherein m=1, 2, 3 or 4 in (R6)m) radicals are independently selected from the group consisting of hydrogen; —NO2; (C1-C10)alkyl; halo(C1-C10)alkyl; —OR13; —NR13R14; or

two R6 groups attached to adjacent carbon atoms (e.g., adjacent carbon atoms on the benzo ring) together with the carbon atoms to which they are attached form a C5-C8 mono-cyclic carbocyclic or heterocyclic ring;

(h3) wherein R11 and R12 are independently selected from the group consisting of hydrogen; (C1-C10)alkyl; heterocyclyl; aryl(C1-C10)alkyl; carboxy(C1-C10)alkyl; and carbo(C1-C10)alkoxy(C1-C10)alkyl; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring;

(n3) provided that aryl is selected from the group consisting of optionally substituted phenyl, biphenyl and naphthyl;

(o3) provided that heterocyclyl is selected from the group consisting of optionally substituted heterocyclyl comprising a 5 to 8 membered ring and comprising one or more ring atoms that are heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur and phosphorus.

According to another embodiment, the substituents of formulas I-1 to I-24 are as follows:

(a4) R2A and R2B are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl; and

(b4) R3A and R3B are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, phenoxymethylene, phenoxyethylene, phenoxypropylene, pyridinyloxymethylene, pyridinyloxyethylene; methylpyridinyloxymethylene, methylpyridinyloxyethylene, pyrimidinyloxymethylene, and pyrimidinyloxyethylene; or R3A and R3B taken together with the carbon to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

two R6 groups attached to adjacent carbon atoms (e.g., adjacent carbon atoms on the benzo ring) together with the carbon atoms to which they are attached form a C4-C10 mono- or bi-cyclic carbocyclic or heterocyclic ring;

wherein the mono- or bi-cyclic carbocyclic or heterocyclic rings optionally may be further substituted with one or more radicals selected from the group consisting of halogen; hydroxy; cyano; nitro; oxo; thioxo; methyl; ethyl; propyl; butyl; pentyl; hexyl; methoxy; ethoxy, propoxy, butoxy, pentoxy, hexyloxy, amino; methylamino; dimethylamino; ethylamino; and diethylamino; or

a pharmaceutically acceptable salt, solvate, or prodrug thereof;

(g4) same as (g3) above;

(h4) same as (h3) above;

(i4) same as (i3) above;

(j4) same as (j3) above;

(k4) same as (k3) above;

(l4) same as (l3) above;

(m4) same as (m3) above;

(n4) same as (n3) above;

(o4) same as (o3) above).

According to another embodiment, the substituents on compounds of formulas I-1 to I-24 are as follows:

two R6 groups attached to adjacent carbon atoms (e.g., adjacent carbon atoms on the benzo ring) together with the carbon atoms to which they are attached form a C5-C10 mono- or bi-cyclic carbocyclic or heterocyclic ring;

(g6) wherein R11 and R12 are independently selected from the group consisting of hydrogen; —CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; carboxyalkyl; carboalkoxyalkyl; cycloalkyl; cyanoalkyl; —OR9; —NR9R10; —SR9; —S(O)R9; —SO2R9; —SO3R9; —CO2R9; and —CONR9R10; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring;

wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or

wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and

(g7) wherein R11 and R12 are independently selected from the group consisting of hydrogen; —CN; halogen; oxo; alkyl; alkenyl; alkynyl; aryl; heterocyclyl; arylalkyl; carboxyalkyl; carboalkoxyalkyl; cycloalkyl; cyanoalkyl; —OR9; —NR9R10; —SR9; —S(O)R9; —SO2R9; —SO3R9; —CO2R9; and —CONR9R10; or R11 and R12 together with the carbon atom to which they are attached form a cyclic ring; and

wherein R13 and R14 together with the nitrogen atom to which they are attached form a mono- or polycyclic heterocyclyl that is optionally substituted with one or more radicals selected from the group consisting of oxo, carboxy, and quaternary salts; or

wherein R14 and R15 together with the nitrogen atom to which they are attached form a cyclic ring; and

(k7) wherein R19 and R20 are independently selected from the group consisting of hydrogen and alkyl;

(l7) same as (l1) above;

(m7) same as (m1) above.

According to another embodiment, the substituents of compounds of formulas I-1 to I-24 are as follows:

(a8) same as (a7) above;

(b8) same as (b7) above;

(c8) wherein R5A is:

wherein R5 is as defined in (c7) above and t is 1, 2, 3, 4 or 5;

(d8) same as (d7) above;

(e8) same as (e7) above;

(f8) same as (f7) above;

(g8) same as (g7) above;

(h8) same as (h7) above;

(i8) same as (i7) above;

(j8) same as (j7) above;

(k8) same as (k7) above;

(l8) same as (l7) above;

(m8) same as (m7) above.

According to another embodiment, the substituents of compounds of formulas I-1 to I-24 are as follows:

(a9) same as (a8) above;

(b9) same as (b8) above;

(c9) wherein R5A is:

wherein R5 is as defined in (c8) above;

(d9) same as (d8) above;

(e9) same as (e8) above;

(f9) same as (f8) above;

(g9) same as (g8) above;

(h9) same as (h8) above;

(i9) same as (i8) above;

(j9) same as (j8) above;

(k9) same as (k8) above;

(l9) same as (l8) above;

(m9) same as (m8) above.

According to another embodiment, the substituents of compounds of formulas I-1 to I-24 are as follows:

(a10) same as (a8) above;

(b10) same as (b8) above;

(c10) wherein R5A is:

wherein R5 is as defined in (c8) above;

(d10) same as (d9) above;

(e10) same as (e9) above;

(f10) same as (f9) above;

(g10) same as (g9) above;

(h10) same as (h9) above;

(i10) same as (i9) above;

(j10) same as (j9) above;

(k10) same as (k9) above;

(l10) same as (l9) above;

(m10) same as (m9) above.

Preferably, in each of the various embodiments of the invention described above, in each of Formulas I-1 to I-24 and in each of the benzothiepine intermediates and products (containing a benzothiepene 7 membered ring described in Schemes 1-7), at least one or more of the following conditions are satisfied:

(1) j is 1 or 2. Preferably, j is 2; and/or

(2) The substituents at the 2-position of the benzothiepine are independently selected from the group consisting of hydrogen and alkyl. Preferably, these substituents are hydrogen; and/or

(3) The substituents at the 3-position of the benzothiepine are independently selected from the group consisting of hydrogen and alkyl. Preferably, these substituents are independently selected from the group consisting of C1-6 alkyls. More preferably, these substituents are selected from the group consisting of ethyl, propyl and butyl. Still more preferably, either (a) one of these 3-position substituents is ethyl and the other is n-butyl, or (b) both of these 3-position substituents are n-butyl; and/or

(4) The substituents at the 5-position of the benzothiepene is aryl or substituted aryl. Preferably, the aryl is phenyl that is optionally substituted at the meta and/or the para position. More preferably, the substitution at the meta and/or the para position of the phenyl is glucuronidated or monosubstituted with a radical selected from the group consisting of —R5, —OR13, —NR13C(O)R14, —NR13C(O)NR14R15, —NR13CO2R14, —OC(O)R13, —OC(O)NR13R14, —NR13SOR14, —NR13SO2R14, —NR13SONR14R15, and —NR13SO2NR14R15 wherein R5, R13, R14 and R15 are as previously defined; and/or

(6) Only one of R5A or R5B is hydrogen; and/or

(7) One or more substituents R6 of the benzo ring of the benzothiepine are independently selected from the group consisting of halogen, —OR13 and —NR13R14, wherein R13 and R14 are as previously defined. Preferably, the substituents of the benzo ring are independently selected from the group consisting of halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino. Still more preferably, the substituents are independently selected from the group consisting of chloro, methoxy and dimethylamino.

Alternative Forms Of Novel Compounds

Also included in the family of compounds of Formulas I-1 to I-24 are (a) the stereoisomers thereof, (b) the pharmaceutically-acceptable salts thereof (c) the tautomers thereof, (d) the protected acids and the conjugate acids thereof, and (e) the prodrugs thereof.

(a) The Stereoisomers

The stereoisomers of these compounds may include, but are not limited to, enantiomers, diastereomers, racemic mixtures and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention. Isomers may include geometric isomers. Examples of geometric isomers includes, but are not limited to, cis isomers or trans isomers across a double bond. Other isomers are contemplated among the compounds of the present invention. The isomers may be used either in pure form or in admixture with other isomers of the inhibitors described above.

Suitable pharmaceutically-acceptable base addition salts of compounds of Formulas I-1 to I-24 include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, and trimethylamine. The above salts may be prepared by conventional means from the corresponding compounds of the invention by reacting, for example, the appropriate acid or base with the compounds of Formulas I-1 to I-24.

(c) The Tautomers

Tautomers of the aforementioned compounds (Formulas I-1 to I-24) are encompassed by the present invention. Thus, for example, (even though not shown) a carbonyl includes its hydroxy tautomer.

(d) The Protected Acids and the Conjugate Acids

The protected acids of these compounds (Formulas I-1 to I-24) include, but are not limited to, protected acids such as esters, hydroxyamino derivatives, amides and sulfonamides. Thus, for example, primary and secondary amines can be reacted with carboxylic acid substituted forms of the compounds of Formulas I-1 to I-24 to form amides which can be useful as prodrugs. Preferred amines are heterocyclicamines, including optionally substituted aminothiazoles, optionally substituted amino-isoxazoles, optionally substituted aminopyridines, optionally substituted aniline derivatives, optionally substituted sulfonamides, optionally substituted aminocarboxylic acids, and the like. The esters, hydroxyamino derivatives and sulfonamides can be prepared from the acids by methods known to one skilled in the art.

(e) The Prodrugs

The present invention includes the prodrugs of the compounds of Formulas I-1 to I-24.

Dosages And Treatment Regimen

Dosage levels of the compounds of Formulae I-1 to I-24 typically are from about 0.001 mg to about 10,000 mg daily, preferably from about 0.005 mg to about 1,000 mg daily, more preferably from about 0.008 mg to about 100 mg daily, and even more preferably from about 0.05 mg to about 50 mg daily. On the basis of mg/kg daily dose, either given in a single or divided doses, dosages typically range from about 0.001/75 mg/kg to about 10,000/75 mg/kg, preferably from about 0.005/75 mg/kg to about 1,000/75 mg/kg, more preferably from about 0.008/75 to about 100/75 mg/kg, and even more preferably from about 0.05/75 mg/kg to about 50/75 mg/kg.

The total daily dose of each drug can be administered to the patient in a single dose, or in multiple subdoses. Typically, subdoses can be administered two to six times per day, preferably two to four times per day, and even more preferably two to three times per day. Doses can be in immediate release form or sustained release form sufficiently effective to obtain the desired control over the hyperlipidemic condition.

The dosage regimen to prevent, treat, give relief from, or ameliorate a hyperlipidemic condition or disorder, or to otherwise protect against or treat high cholesterol blood (or plasma) levels with the combinations and compositions of the present invention is selected in accordance with a variety of factors. These factors include, but are not limited to, the type, age, weight, sex, diet, and medical condition of the subject, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profiles of the particular inhibitors employed, whether a drug delivery system is utilized, and whether the inhibitors are administered with other active ingredients. Thus, the dosage regimen actually employed may vary widely and therefore deviate from the preferred dosage regimen set forth above.

Initial treatment of a patient suffering from a hyperlipidemic condition or disorder can begin with the dosages indicated above. Treatment generally should be continued as necessary over a period of several weeks to several months or years until the hyperlipidemic condition or disorder has been controlled or eliminated. Patients undergoing treatment with the combinations of the compounds disclosed herein can be routinely monitored, for example, by measuring serum LDL and total cholesterol levels by any of the methods well-known in the art to determine the effectiveness of the combination therapy. Continuous and intermittent analysis of such data permits modification of the treatment regimen during therapy so that optimal therapeutically effective amounts of each type of inhibitor are administered at any time for an appropriate duration of time. In this way, the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amount of inhibitor that exhibits satisfactory therapeutic effectiveness is administered, and so that administration is continued only so long as is necessary to successfully treat or otherwise ameliorate the hyperlipidemic condition. Of course, maintenance dosing to keep the hyperlipidemic condition under the desired control may be instituted as necessary.

Pharmaceutical Compositions

For the prophylaxis or treatment of the conditions and disorders referred to above, the compounds of this invention (Formulas I-1 to I-24) can be administered as the compound per se. Alternatively, pharmaceutically-acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to that of the parent compound.

The compounds of the present invention also can be administered with an acceptable carrier in the form of a pharmaceutical composition. The carrier must be acceptable in the sense of being compatible with the other ingredients of the composition and must not be intolerably deleterious to the recipient. The carrier can be a solid or a liquid, or both, and preferably is formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from about 0.05% to about 95% by weight of the active compound(s) based on a total weight of the dosage form. Other pharmacologically active substances can also be present, including other compounds useful in the treatment of a hyperlipidemic condition.

The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a therapeutically effective dose for the treatment intended. The active compounds and compositions, for example, may be administered orally, sublingually, nasally, pulmonarily, mucosally, parenterally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically. Unit dose formulations, particularly orally administrable unit dose formulations such as tablets or capsules, generally contain, for example, from about 0.001 to about 500 mg, preferably from about 0.005 mg to about 100 mg, and more preferably from about 0.01 to about 50 mg, of the active ingredient. In the case of pharmaceutically acceptable salts, the weights indicated above for the active ingredient refer to the weight of the pharmaceutically active ion derived from the salt.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, a capsule, a suspension, an emulsion, a paste, a solution, a syrup or other liquid form. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. If administered by mouth, the compounds may be admixed with, for example, lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.

Oral delivery of the compounds of the present invention can include formulations, as are well known in the art, to provide immediate delivery or prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. Immediate delivery formulations include, but are not limited to, oral solutions, oral suspensions, fast-dissolving tablets or capsules, sublingual tablets, disintegrating tablets and the like. Prolonged or sustained delivery formulations include, but are not limited to, pH sensitive release of the active ingredient from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. The intended effect is to extend the time period over which the active drug molecule is delivered to the site of action (for example, the ileum for ASBT inhibitors) by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester. Such prolonged or sustained delivery formulations preferably are in a dispersed form at the time they reach the ileum. Other examples of suitable coatings include products known as Eudragit S provided in a thickness sufficient to release the active ingredient in the desired location of the GI tract. Preferably, in the case of an Eudragit S coating, the coating has a thickness from about 10 to about 50 microns, more preferably from about 20 to 45 microns, even more preferably from about 25 to about 43 microns and most preferably from about 30 to about 40 microns. The coating of Eudragit S may be combined with other coating materials known as Eudragit L. Formulations of ASBT inhibitor(s), such as tablets coated with Eudragit S and/or Eudragit L, can be readily formed by those of ordinary skill.

Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the inhibitor(s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the inhibitor(s) with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the inhibitors, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made, for example, by molding the powdered compound in a suitable machine.

Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the inhibitors in an inert base such as gelatin and glycerin or sucrose and acacia.

Formulations for parenteral administration, for example, may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, cone oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

Pharmaceutically acceptable carriers encompass all the foregoing and the like. The pharmaceutical compositions of the invention can be prepared by any of the well-known techniques of pharmacy, such as admixing the components. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (1975); Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980); and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington (1999); U.S. Pharamacopeia (Twenty-First Revision—USP XXI) National Formulary (Sixteenth Edition—XVI), United States Pharmacopeial Convention, Inc., Rockville, Md. (1985) and its later editions; and Remington's Pharmaceutical Sciences. 16th Edition, Arthur Osol, Editor and Chairman of the Editorial Board, Mack Publishing Co., Easton, Pa. (1980) and its later editions.

Methods Of Use

The present invention also includes methods for the treatment of one or more hyperlipidemic condition(s) in a subject. One such method comprises the step of administering to a subject in need thereof, a therapeutically effective amount of one or more compounds of Formulas I-1 to I-24.

The present invention further includes methods for the treatment of gallstones in a subject. An exemplary method for the treatment of gallstones comprises the step of administering to a subject in need thereof, a therapeutically effective amount of one or more compound(s) of Formulas I-1 to I-24.

The methods and compounds of the present invention may be used alone or in conjunction with additional therapies and/or compounds known to those skilled in the art in the prevention or treatment of hyperlipidemia Alternatively, the methods and compounds described herein may be used, partially or completely, in conjunctive therapy. By way of example, the compounds may be administered alone or in conjunction with other anti-hyperlipidemic agents, such as together with HMG-CO-A reductase inhibitors, bile acid sequestering agents, fibric acid derivatives, nicotinic acid, and/or probucol. The above-noted combination therapeutic agents may be provided in a kit.

Terms

As used herein, various terms are defined below.

When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.

The term “subject” as used herein includes mammals (eg., humans and animals).

The term “treatment” includes any process, action, application, therapy, or the like, for improving the subject's medical condition, directly or indirectly, including, but not limited to, hyperlipidemia or conditions associated with hyperlipidemia.

The terms “prophylaxis” and “prevention” include either preventing the onset of a clinically evident hyperlipidemic condition or disorder altogether or preventing the onset of a preclinically evident stage of a hyperlipidemic condition or disorder in an individual. These terms encompass the prophylactic treatment of a subject at risk of developing a hyperlipidemic condition or disorder such as, but not limited to, atherosclerosis and hypercholesterolemia.

The term “combination therapy” or “co-therapy” means the administration of two or more therapeutic agents to treat a hyperlipidemic condition and/or disorder, for example atherosclerosis and hypercholesterolemia. Such administration encompasses co-administration of two or more therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent. In addition, such administration encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the hyperlipidemic condition.

The phrase “therapeutically-effective” means the amount of each agent administered that will achieve the goal of improvement in hyperlipidemic condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.

The term “pharmaceutically acceptable” means that the subject item is appropriate for use in a pharmaceutical product.

The term “prodrug” includes a compound that is a drug precursor that, following administration to a subject and subsequent absorption, is converted to an active species in vivo. Conversion to the active, species in vivo is typically via some process, such as metabolic conversion. An example of a prodrug is an acylated form of the active compound.

The term “ASBT inhibitor” includes a compound capable of inhibiting absorption of bile acids from the intestine into the circulatory system of a mammal, indicating that of a human. This includes increasing the fecal excretion of bile acids, as well as reducing the blood plasma or serum concentrations of cholesterol and cholesterol ester, and more specifically, reducing LDL and VLDL cholesterol.

Where the term “alkyl” is used, either alone or within other terms such as “haloalkyl”, and “hydroxyalkyl”, it includes linear or branched radicals having one to about twenty carbon atoms, preferably, one to about twelve carbon atoms, more preferably, “lower alkyl” radicals having one to about six carbon atoms and, even more preferably, lower alkyl radicals having one to three carbon atoms. Examples of such radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.

Where the term “alkenyl” is used, either alone or within other terms such as “arylalkenyl”, it includes linear or branched radicals having at least one carbon-carbon double bond in a radical having from two to about twenty carbon atoms, preferably, from two to about twelve carbon atoms, and more preferably “lower alkenyl” radicals having from two to about six carbon atoms. Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.

The terms “alkenyl” and “lower alkenyl”, include radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.

The term “alkynyl” includes, but is not limited to, linear or branched radicals having from two to about twenty carbon atoms or, preferably, from two to about twelve carbon atoms, more preferably “lower alkynyl” radicals having from two to about ten carbon atoms, most preferably lower alkynyl radicals having from two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.

The term “cycloalkyl” includes, but is not limited to, saturated carbocyclic radicals having from three to about twelve carbon atoms, more preferably “lower cycloalkyl” radicals having from three to about ten carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “cycloalkyl” additionally encompasses spiro systems wherein the cycloalkyl ring has a carbon ring atom in common with the seven-membered heterocyclic ring of the benzothiepene.

The term “cycloalkenyl” includes, but is not limited to, unsaturated carbocyclic radicals having at least one double bond and having from three to twelve carbon atoms and more preferably “lower cycloalkenyl” radicals having from four to about ten carbon atoms. Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called “cycloalkyldienyl”. Examples of cycloalkenyl radicals includes, but is not limited to, cyclobutenyl, cyclopentenyl and cyclohexenyl.

The terms “halo” and “halogen” include, but are not limited to, halogen atoms such as fluorine, chlorine, bromine or iodine. The term “haloalkyl” includes radicals wherein any one or more of the alkyl carbon atoms is substituted with a halogen atom. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same or different halogen atoms. “Lower haloalkyl” includes radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl” includes alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.

The term “hydroxyalkyl” includes, but is not limited to, linear or branched alkyl radicals preferably having from one to about ten carbon atoms, more preferably “lower hydroxyalkyl” radicals having from one to six carbon atoms and even more preferably lower hydroxyalkyl radicals having from one to three carbon atoms wherein one or more of the carbon atoms are substituted with one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.

The term “aryl” includes, but is not limited to, a carbocyclic aromatic system containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused. The term “aryl” includes aromatic radicals such as cyclopentodienyl phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, and anthracenyl. Further, “aryl” group may optionally have from one to three substituents such as lower alkyl, hydroxy, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino.

“Heteroaryl” radicals can include, but are not limited to, fused or unfused radicals, particularly 3-10 membered fused or unfused radicals. Preferred examples of heteroaryl radicals include benzofuryl, 2,3-dihydrobenzofuryl, benzothienyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, furyl, and pyrazinyl. More preferred heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur, nitrogen and oxygen such as thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl or pyrazinyl. The term “heteroaryl” includes, but is not limited to, a fully unsaturated heterocyclyl. The term “heteroaryl” includes all positional isomers.

In either the “heterocyclyl” or the “heteroaryl” radical, the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.

The term “triazolyl” includes, but is not limited to, all positional isomers. In all other heterocyclyl and heteroaryl which contain more than one ring heteroatom and for which isomers are possible, such isomers are included in the definition of said heterocyclyl and heteroaryl.

The term “quaternary heterocyclyl” includes, but is not limited to, a heterocyclyl in which one or more of the heteroatoms, for example, nitrogen, sulfur, phosphorus or oxygen, has such a number of bonds that it is positively charged (and therefore the term is intended to encompass both ternary and quaternary positively charged structures). The point of attachment of the quaternary heterocyclyl to the molecule of interest can be at a heteroatom or elsewhere.

The term “quaternary heteroaryl” includes, but is not limited to, a heteroaryl in which one or more of the heteroatoms, for example, nitrogen, sulfur, phosphorus or oxygen, has such a number of bonds that it is positively charged (and therefore the term is intended to encompass both ternary and quaternary positively charged structures). The point of attachment of the quaternary heteroaryl to the molecule of interest can be at a heteroatom or elsewhere.

The term “oxo” includes, but is not limited to, an oxygen with two bonds.

The term “polyalkyl” includes, but is not limited to, a branched or straight hydrocarbon chain having a molecular weight up to about 20,000 gms, more preferably up to about 10,000 gms, and most preferably up to about 5,000 gms.

The term “polyether” includes, but is not limited to, a polyalkyl wherein one or more carbons are replaced by oxygen, wherein the polyether has a molecular weight up to about 20,000 gms, more preferably up to about 10,000 gms, and most preferably up to about 5,000 gms.

The term “polyalkoxy” includes, but is not limited to, a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight up to about 20,000 gms, more preferably up to about 10,000 gms, and most preferably up to about 5,000 gms.

The term “carbohydrate residue” includes, but is not limited to, residues derived from carbohydrates, but is not limited to, mono-, di-, tri-, tetra- and polysaccharides wherein the polysaccharides can have a molecular weight of up to about 20,000 gms, for example, hydroxypropyl-methylcellulose or chitosan residue; compounds derived from aldoses and ketoses with from 3 to 7 carbon atoms and which belong to the D- or L-series; aminosugars; sugar alcohols; and saccharic acids. Nonlimiting specific examples of such carbohydrates include glucose, mannose, fructose, galactose, ribose, erythrose, glycerinaldehyde, sedoheptulose, glucosamine, galactosamine, glucoronic acid, galacturonic acid, gluconic acid, galactonic acid, mannoic acid, glucamine, 3-amino-1,2-propanediol, glucaric acid and galactaric acid.

The term “peptide residue” includes, but is not limited to, polyamino acid residue containing up to about 100 amino acid units.

The term “polypeptide residue” includes, but is not limited to, a polyamino acid residue containing from about 100 amino acid units to about 1000 amino acid units, more preferably from about 100 amino acid units to about 750 amino acid units, and even more preferably from about 100 amino acid units to about 500 amino acid units.

The term “alkylammoniumalkyl” includes, but is not limited to, an —NH2 group or a mono-, di- or tri-substituted amino group, any of which is bonded to an alkyl wherein said alkyl is bonded to the molecule of interest.

The term “sulfo” includes, but is not limited to, a —SO2— group, a —SO3H group, and its salts.

The term “sulfoalkyl” includes, but is not limited to, an alkyl group to which a sulfonate group is bonded, wherein said alkyl is bonded to the molecule of interest.

The term “aralkyl” includes, but is not limited to, aryl-substituted alkyl radicals, preferably “lower aralkyl” radicals having aryl radicals attached to alkyl radicals having from one to six carbon atoms, and even more preferably lower aralkyl radicals having phenyl attached to alkyl portions having from one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be optionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term “arylalkenyl” includes aryl-substituted alkenyl radicals. Preferable arylalkenyl radicals are “lower arylalkenyl” radicals having aryl radicals attached to alkenyl radicals having from one to ten carbon atoms.

The term “heterocyclylalkyl” includes, but is not limited to, an alkyl radical that is substituted with one or more heterocyclyl groups. Preferable heterocyclylalkyl radicals are “lower heterocyclylalkyl” radicals having from one or more heterocyclyl groups attached to an alkyl radical having from one to ten carbon atoms.

The term “heteroarylalkyl” includes, but is not limited to, an alkyl radical that is substituted with one or more heteroaryl groups. Preferable heteroarylalkyl radicals are “lower heteroarylalkyl” radicals having from one or more heteroaryl groups attached to an alkyl radical having from one to ten carbon atoms.

The term “quaternary heterocyclylalkyl” includes, but is not limited to, an alkyl radical that is substituted with one or more quaternary heterocyclyl groups. Preferable quaternary heterocyclylalkyl radicals are “lower quaternary heterocyclylalkyl” radicals having from one or more quaternary heterocyclyl groups attached to an alkyl radical having from one to ten carbon atoms.

The term “quaternary heteroarylalkyl” includes, but is not limited to, an alkyl radical that is substituted with one or more quaternary heteroaryl groups. Preferable quaternary heteroarylalkyl radicals are “lower quaternary heteroarylalkyl” radicals having from one or more quaternary heteroaryl groups attached to an alkyl radical having from one to ten carbon atoms.

The term “alkylheteroarylalkyl” includes, but is not limited to, a heteroarylalkyl radical that is substituted with one or more alkyl groups. Preferable alkylheteroarylalkyl radicals are “lower alkylheteroarylalkyl” radicals with alkyl portions having from one to ten carbon atoms.

The term “alkoxy” includes, but is not limited to, an alkyl radical which is attached to the molecule of interest by oxygen, such as a methoxy radical. More preferred alkoxy radicals are “lower alkoxy” radicals having from one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, iso-propoxy, butoxy and tert-butoxy.

The term “carboxy” includes, but is not limited to, the carboxy group, —CO2H, and its salts.

The term “carboxyalkyl” includes, but is not limited to, an alkyl radical that is substituted with one or more carboxy groups. Preferable carboxyalkyl radicals are “lower carboxyalkyl” radicals having one or more carboxy groups attached to an alkyl radical having from one to six carbon atoms.

The term “carboxyheterocyclyl” includes, but is not limited to, a heterocyclyl radical that is substituted with one or more carboxy groups.

The term “carboxyheteroaryl” includes, but is not limited to, a heteroaryl radical that is substituted with one or more carboxy groups.

The term “carboalkoxyalkyl” includes, but is not limited to, an alkyl radical that is substituted with one or more alkoxycarbonyl groups. Preferable carboalkoxyalkyl radicals are “lower carboalkoxyalkyl” radicals having one or more alkoxycarbonyl groups attached to an alkyl radical having from one to six carbon atoms.

The term “carboxyalkylamino” includes, but is not limited to, an amino radical that is mono- or di-substituted. When used in combination, for example “alkylaryl” or “arylalkyl,” the individual terms “alkyl” and “aryl” listed above have the meaning indicated above.

The term “acyl” includes, but is not limited to, an organic acid group in which the hydroxy of the carboxy group has been removed. Examples of acyl groups include, but are not limited to, acetyl and benzoyl.

The term “hydrocarbyl” refers to radicals consisting exclusively of the elements carbon and hydrogen. These radicals include, for example, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and aryl moieties. These radicals also include alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Preferably, these moieties comprise 1 to 20 carbon atoms, 1-10 carbons or 1-6 carbons.

The term “a substituted hydrocarbyl” refers to a hydrocarbyl radical that is substituted with a group comprising at least one atom other than carbon, such as but not limited to, halogen, oxygen, nitrogen, sulfur and phosphorus. Examples of such substituted hydrocarbyl include hydrocarbyl radicals substituted with groups such as, but not limited to, lower alkoxy such as methoxy, ethoxy, and butoxy, halogen such as chloro and fluoro; ethers; acetals; ketals; esters; heterocyclyl such as furyl and thienyl; alkanoxy; hydroxy, protected hydroxy, acyl; acyloxy; nitro; cyano; amino; and amido. Substituted hydrocarbyl also includes hydrocarbyl radicals in which a carbon chain atom is replaced with a heteroatom such as nitrogen, oxygen, sulfur, or a halogen.

The term “sugar protecting group” means a protecting group on one or more hydroxy groups of a given sugar. Examples of such “sugar protecting groups” include, but are not limited to, acetyl, trialkylsilyl, alkyl (e.g, methyl), alkoxy (e.g., methoxy, ethoxy), tetrahydropyranyl (THP), etc.

Abbreviations used herein have the following meanings:

TERM

DEFINITION

THF

tetrahydrofuran

PTC

phase transfer catalyst

Aliquart 336

methyltricaprylylammonium chloride

MCPBA

m-chloroperbenzoic acid

Celite

a brand of diatomaceous earth filtering aid

DMF

Dimethylformamide

DME

-ethylene glycol dimethyl ether

BOC

t-butoxycarbonyl group

Me

Methyl

Et

Ethyl

Bu

Butyl

EtOAc

Ethyl acetate

Et2O

diethyl ether

CH2Cl2

methylene chloride

MgSO4

magnesium sulfate

NaOH

sodium hydroxide

CH3OH

Methanol

HCl

hydrochloric acid

NaCl

sodium chloride

NaH

sodium hydride

LAH

lithium aluminum hydride

LiOH

lithium hydroxide

Na2SO3

sodium sulfite

NaHCO3

sodium bicarbonate

DMSO

Dimethylsulfoxide

KOSiMe3

potassium trimethylsilanolate

PEG

polyethylene glycol

MS

Mass spectrometry

HRMS

high resolution mass spectrometry

ES

Electrospray

NMR

nuclear magnetic resonance spectroscopy

GC

gas chromatography

MPLC

medium pressure liquid chromatography

HPLC

high pressure liquid chromatography

RPHPLC

reverse phase high pressure liquid chromatography

RT

Room temperature

h or hr

hour(s)

Min

minute(s)

Biological Evaluation

The inhibitor concentration of the compounds of the present invention is to be determined by the following assays. These assays are to be performed in vitro and in animal models.

In Vitro Assay of Compounds that Inhibit ASBT-Mediated Uptake of [14C]-Taurocholate (TC) in H14 Cells

Anesthetize male wistar rats (200-300 g) with inactin @100 mg/kg. Cannulate bile ducts with a 10″ length of PE10 tubing. Expose the small intestine and lay out on a gauze pad. Insert a canulae (⅛″ luer lock, tapered female adapter) at 12 cm from the junction of the small intestine and the cecum. Cut a slit at 4 cm from this same junction (utilizing a 8 cm length of ileum). Use 20 mL of warm Dulbecco's phosphate buffered saline, pH 6.5 (“PBS”) to flush out the intestine segment. Cannulate the distal opening with a 20 cm length of silicone tubing (0.02″ I.D.×0.037″ O.D.). Hook up the proximal cannulae to a peristaltic pump and wash the intestine for 20 minutes with warm PBS at 0.25 ml/minute. Continuously monitor the temperature of the gut segment.

At the start of the experiment, load 2.0 mL of control sample ([14C]-taurocholate @0.05 mi/mL with 5 mM cold taurocholate) into the gut segment with a 3 mL syringe and begin bile sample collection. Infuse control sample at a rate of 0.25 ml/minute for 21 minutes. Collect bile sample fractions every 3 minutes for the first 27 minutes of the procedure. After the 21 minutes of sample infusion, wash out the ileal loop with 20 mL of warm PBS (using a 30 mL syringe), and then wash out the loop for 21 minutes with warm PBS at 0.25 ml/minutes. Initiate a second perfusion as described above but with test compound being administered as well (21 minutes administration followed by 21 minutes of wash out) and sample bile every 3 minutes for the first 27 minutes. If necessary, conduct a third perfusion as above that containing the control sample.

Measurement of Hepatic Cholesterol Concentration (HEPATIC CHOL)

Weigh liver tissue and homogenize in chloroform:methanol (2:1). After homogenization and centrifugation, separate the supernatant and dry under nitrogen. Dissolve the residue in isopropanol and measure the cholesterol content enzymatically, using a combination of cholesterol oxidase and peroxidase, as described by Allain, C. A., et al., Clin. Chem. 20, 470 (1974).

Measurement of Hepatic HMG CoA-Reductase Activity (HMG COA)

Prepare Hepatic microsomes by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. Resuspend the final pelleted material in buffer and assay an aliquot for HMG CoA reductase activity by incubating for 60 minutes at 37° C. in the presence of 14C-HMG-CoA (Dupont-NEN). Stop the reaction by adding 6N HCl followed by centrifugation. Separate an aliquot of the supernatant by thin-layer chromatography, and scrape off the plate the spot corresponding to the enzyme product. Extract and determine radioactivity by scintillation counting. (See Akerlund, J. and Bjorkhem, I., J. Lipid Res. 31, 2159(1990)).

Prepare hepatic microsomes by homogenizing liver samples in a phosphate/sucrose buffer, followed by centrifugal separation. Resuspend the final pelleted material in buffer and assay an aliquot for cholesterol 7α-hydroxylase activity by incubating for 5 minutes at 37° C. in the presence of NADPH. Following extraction into petroleum ether, evaporate the organic solvent and dissolve the residue in acetonitrile/methanol. Separate the enzymatic product by injecting an aliquot of the extract onto a C18 reversed phase HPLC column and quantitate the eluted material using UV detection at 240 nm. (See Horton, J. D., et al., J. Clin. Invest. 93, 2084(1994).)

Rat Gavage Assay

Administer ASBT inhibitors to male Wister rats (275-300 g) using an oral gavage procedure. Administer drug or vehicle (0.2% Tween 80 in water) once a day (9:00-10:00 am.) for 4 days at varying dosages in a final volume of 2 mL per kilogram of body weight. Collect total fecal samples during the final 48 hours of the treatment period and analyze for bile acid content using an enzymatic assay as described below. Determine compound efficacy by comparison of the increase in fecal bile acid (FBA) concentration in treated rats to the mean FBA concentration of rats in the vehicle group.

Measurement of Fecal Bile Acid Concentration (FBA)

Collect total fecal output from individually housed hamsters is collected for 24 or 48 hours, dried under a stream of nitrogen, pulverized and weighed. Approximately 0.1 gram is weighed out and extracted into an organic solvent (butanol/water). Following separation and drying, the residue is dissolved in methanol and the amount of bile acid present is measured enzymatically using the 3α-hydroxysteroid steroid dehydrogenase reaction with bile acids to reduce NAD. (See Mashige, F., et al., Clin. Chem. 27, 1352 (1981)).

Prepare hamster liver and rat intestinal microsomes from tissue as described previously (See J. Biol. Chem. 255, 9098 (1980)) and use as a source of ACAT enzyme. The assay consists of a 2.0 mL incubation containing 24 μM Oleoyl-CoA (0.05 μCi) in a 50 mM sodium phosphate, 2 mM DTT pH 7.4 buffer containing 0.25 % BSA and 200 μg of microsomal protein. Initiate the assay by the addition of oleoyl-CoA. Allow the reaction to proceed for 5 minutes at 37° C. and terminate it by the addition of 8.0 mL of chloroform/methanol (2:1). To the extraction, add 125 μg of cholesterol oleate in chloroform methanol to act as a carrier and the organic and separate the aqueous phases of the extraction by centrifugation after thorough vortexing. Take the chloroform phase to dryness and then spot on a silica gel 60 thin layer chromatography plate and develop in hexane/ethyl ether (9:1). Determine the amount of cholesterol ester formed by measuring the amount of radioactivity incorporated into the cholesterol oleate spot on the thin layer chromatography plate with a Packard instaimager.

As various changes could be made in the above methods and apparatus without departing from the scope of the invention, it is intended that all matter contained in the above description be interpreted as illustrative and not in a limiting sense. All documents, books, patents, references and publications mentioned in this application are expressly incorporated by reference in their entirety as if fully set forth at length.

Dog Model for the Evaluation of Lipid-Lowering Drugs

Obtain male beagle dogs weighing 6-12 kg from a vendor, such as Marshall farms. Feed each dog once a day for two hours and give water ad libitum. Randomly assign dogs to dosing groups consisting of 6 to 12 dogs each, corresponding to: vehicle, i.g.; 1 mg/kg, i.g.; 2 mg/kg, i.g.; 4 mg/kg, i.g.; 2 mg/kg, p.o. (powder in capsule). Perform intra-gastric dosing of a therapeutic compound dissolved in aqueous solution (for example, 0.2% Tween 80 solution (polyoxyethylene mono-oleate, Sigma Chemical Co., St. Louis, Mo.)) using a gavage tube. Prior to initiating dosing, draw blood samples from the cephalic vein before the morning feeding in order to evaluate serum cholesterol (total and HDL) and triglycerides. For several consecutive days, dose animals in the morning prior to feeding. Thereafter, allow animals to eat for two hours before remaining food is removed. Collect feces over a 2-day period at the end of the study and analyze for bile acid or lipid content. Collect blood samples at the end of the treatment period for comparison with pre-study serum lipid levels. Determine statistical significance using the standard Student's T-test, with p<0.05.

Measure total cholesterol in a 96-well format using a Wako enzymatic diagnostic kit (Cholesterol CII) (Wako Chemicals, Richmond, Va.), utilizing the cholesterol oxidase reaction to produce hydrogen peroxide, which is measured calorimetrically. Prepare a standard curve from 0.5 to 10 mg cholesterol in the first two columns of the plate. Add the serum samples (20-40 mL, depending on the expected lipid concentration) or known serum control samples to individual wells in duplicate. Add water to bring the volume to 100 mL in each well. Add a 100-ml aliquot of color reagent to each well, and read the plates at 500 nm after a 15-minute incubation at 37° C.

HDL cholesterol was assayed using Sigma kit No. 352-3 (Sigma Chemical Co., St. Louis, Mo.), which utilizes dextran sulfate and Mg2+ to selectively precipitate LDL and VLDL. Add a volume of 150 mL of each serum sample to individual microfuge tubes, followed by 15 mL of HDL cholesterol reagent (Sigma 352-3). Mix samples and centrifuge at 5000 rpm for 5 minutes. Then mix a 50 mL aliquot of the supernatant with 200 mL of saline and assay using the same procedure as for total cholesterol measurement.

Measure triglycerides using Sigma kit No. 337 in a 96-well plate format. This procedure will measure the release glycerol from triglycerides with lipoprotein lipase. Use standard solutions of glycerol (Sigma 339-11) ranging from 1 to 24 mg to generate the standard curve. Add serum samples (20-40 mL, depending on the expected lipid concentration) to wells in duplicate. Add water to bring the volume to 100 mL in each well and then add 100 mL of color reagent to each well. After mixing and a 15-minutes of incubation, read the plates at 540 nm and calculate the triglyceride values from the standard curve. Run a replicate plate using a blank enzyme reagent to correct for any endogenous glycerol in the serum samples.

Dog Fecal Bile Acid Measurement

Collect fecal samples to determine the fecal bile acid (FBA) concentration for each animal. Obtain fecal collections during the final 48 hours of the study, for two consecutive 24-hour periods between 9:00 am. and 10:00 a.m. each day, prior to dosing and feeding. Weigh the separate two-day collections from each animal, combine and homogenize with distilled water in a processor (Cuisinart) to generate a homogeneous slurry. Extract a sample of 1.4 g of the homogenate in a final concentration of 50% tertiary butanol/distilled water (2:0.6) for 45 minutes in a 37° C. water bath and centrifuge for 13 minutes at 2000×G.

Determine the concentration of bile acids (mmoles/day) using a 96-well enzymatic assay system. Add a 20-mL aliquot of the fecal extract to two sets each of triplicate wells in a 96-well assay plate. Analyze a standardized sodium taurocholate solution and a standardized fecal extract solution (previously made from pooled samples and characterized for its bile acid concentration) for assay quality control. Similarly add aliquots of sodium taurocholate (20 mL), serially diluted to generate a standard curve, to two sets of triplicate wells. Add a 230-mL reaction mixture containing 1M hydrazine hydrate, 0.1 M pyrophosphate and 0.46 mg/ml NAD to each well. Then add a 50-mL aliquot of 3α-hydroxysteroid dehydrogenase enzyme (HSD; 0.8 units/ml) or assay buffer (0.1 M sodium pyrophosphate) to one of the two sets of triplicates. Obtain all reagents from Sigma Chemical Co., St. Louis, Mo. Following 60 minutes of incubation at room temperature, measure the optical density at 340 nm and calculate the mean of each set of triplicate samples. Use the difference in optical density±HSD enzyme to determine the bile acid concentration (mM) of each sample, based on the sodium taurocholate standard curve. Use the bile acid concentration of the extract, the weight of the fecal homogenate (grams) and the body weight of the animal to calculate the corresponding FBA concentration in mmoles/kg/day for each animal. Substrate the mean FBA concentration (mmoles/kg/day) of the vehicle group from the FBA concentration of each treatment group to determine the increase (delta value) in FBA concentration as a result of the treatment.

Below are various illustrative examples for making various compounds in connection with the invention. The following examples and specific embodiments are provided for illustrative purposes and not intended to limit the scope of the invention.

SPECIFIC EMBODIMENTS

1. A compound comprising a benzothiepene of Formula I-1 or I-2:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof

wherein j is 0, 1 or 2;

wherein m is 0, 1, 2, 3 or 4;

wherein R2A and R2B are independently selected from the group consisting of hydrogen and hydrocarbyl;

wherein R9 and R10 are independently selected from the group consisting of hydrogen; hydrocarbyl; amino; and hydrocarbylamino;

wherein R5 is selected from the group consisting of hydrogen; hydrocarbyl, heterocyclyl; quaternary heterocyclyl; —OR9; —SR9; —S(O)R9; —SO2R9; and —SO3R9;

wherein when R5 is said cycloalkyl, aryl or heterocyclyl, said cycloalkyl, aryl or heterocyclyl are optionally substituted with —NH—X—R or —O—X—R;

wherein X is selected from the group consisting of —(C═O)s-alkyl-; —(C═O)s-alkyl-NH—; —(C═O)s-alkyl-O—; —(C═O)s-alkyl-(C═O)t; and a covalent bond, wherein s and t are independently 0 or 1;

wherein R is selected from the group consisting of monosaccharides, disaccharides, and polysaccharides, wherein said monosaccharides, disaccharides, and polysaccharides are optionally protected with one or more sugar protecting groups;

wherein, in each instance, said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein, in each instance, said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus and combinations thereof.

2. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R2A and R2B are independently selected from the group consisting of hydrogen and alkyl, R3A and R3B are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl and arakyl and R5 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl and aryl.

3. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R5A is aryl optionally substituted with said radical R5 selected from the group consisting of (1)-(69) and (70):

provided that when said R5 is (7), (17) or (24), then said R5A is a left end of said R5 and R5B is a right end of said R5 or vice versa.

4. The compound of embodiment 3 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R5A is phenyl optionally substituted at least at either a para position or a meta position of said phenyl with said radical R5.

5. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein j=2, R2A and R2B are independently selected from the group consisting of hydrogen and alkyl, and R3A and R3B are independently selected from the group consisting of hydrogen and alkyl.

6. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein j=2, at least one of R2A and R2B is hydrogen, and R3A and R3B each are alkyl.

7. The compound of embodiment 6 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R2A=R2B=H and R3A and R3B are independently selected from the group consisting of ethyl, propyl and butyl.

8. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R2A and R2B are independently selected from the group consisting of hydrogen and C1-10 alkyl, R3A and R3B are independently selected from the group consisting of hydrogen and C1-10 alkyl.

9. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R2A and R2B are independently selected from the group consisting of hydrogen and C1-6 alkyl, and R3A and R3B are independently selected from the group consisting of hydrogen and C1-6 alkyl.

10. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R2A and R2B are the same radical.

11. The compound of embodiment 10 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R2A and R2B are the same alkyl radical.

12. The compound of embodiment 10 or a pharmaceutically acceptable salt, solvate or prodrug thereof wherein R2A and R2B are the same radical selected from the group consisting of hydrogen, C1-10 alkyl, C1-10 alkenyl and C1-10 alkynyl.

13. The compound of embodiment 10 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3A and R3B are the same radical.

14. The compound of embodiment 11 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3A and R3B are the same alkyl radical.

15. The compound of embodiment 12 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3A and R3B are the same radical selected from the group consisting of hydrogen, C1-10 alkyl, C1-10 alkenyl and C1-10 alkynyl.

16. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3A and R3B are the same radical.

17. The compound of embodiment 16 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3A and R3B are the same alkyl radical.

18. The compound of embodiment 16 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3A and R3B are the same radical selected from the group consisting of hydrogen, C1-10 alkyl, C1-10 alkenyl and C1-10 alkynyl.

19. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R2A and R2B are the same C1-20 hydrocarbyl radical.

20. The compound of embodiment 19 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R2A and R2B are the same C1-10 hydrocarbyl radical.

21. The compound of embodiment 20 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R2A and R2B are the same C1-6 hydrocarbyl radical.

22. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3A and R3B are the same C1-20 hydrocarbyl radical.

23. The compound of embodiment 22 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3A and R3B are the same C1-10 hydrocarbyl radical.

24. The compound of embodiment 23 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3A and R3B are the same C1-6 hydrocarbyl radical.

25. The compound of embodiment 11 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R2A and R2B are each n-butyl.

26. The compound of embodiment 10 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R2A and R2B are each H.

27. The compound of embodiment 13 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3A and R3B are each H or n-butyl.

28. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein one or more radicals R6 are selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, amino, alkylamino and dialkylamino.

29. The compound of embodiment 28 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein one or more radicals R6 are selected from the group consisting of methoxy, ethoxy and dimethylamino.

30. The compound of embodiment 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein j=2, m=1, one of R5A and R5B is hydrogen and the other of R5A and R5B is a phenyl radical optionally substituted at a para position of said phenyl radical with said radical R5 selected from the group consisting of (1)-(69) and (70):

provided that when said R5 is (7), (17) or (24), then said R5A is a left end of said R5 and R5B is a right end of said R5 or vice versa.

31. The compound of embodiment 1 wherein said benzothiepene comprises the compound of Formula I-17 or I-18:

32. The compound of embodiment 31 wherein said R5 is attached to either a para-position or a meta-position on said phenyl ring attached to the 5-position ring carbon of said benzothiepene compound of said Formulas I-17 or I-18.

33. The compound of embodiment 31 wherein said benzothiepene of said Formula I-17 comprises a member selected from the group consisting

of Formulas I-21 and I-22:

34. The compound of embodiment 33 wherein said benzothiepene of said Formulas I-21 and I-22 comprise Formulas I-9 and I-10, respectively, represented by:

35. The compound of embodiment 31 wherein said benzothiepene of said Formula I-18 comprises a member selected from the group consisting of Formulas I-23, and I-24:

36. The compound of embodiment 35 wherein said benzothiepene of said Formulas I-23 and I-24 comprise Formulas I-19 and I-20, respectively, represented by:

37. The compound of embodiment 35 wherein said R5 is attached to either a meta-position or a para-position on said phenyl ring attached to said 5-position carbon ring of said benzothiepenes of said Formulas I-23 and I-24.

38. The compound of embodiments 31-37 wherein said R5 is selected from the group consisting of (1)-(69) and (70):

wherein when said R5 is said (7), said (17) or said (24), then said R5A represents a left-end of said R5 and said R5B represents a right end of said R5 or vice versa.

39. A method for treating a hyprelipidemic condition in a subject comprising administering to said subject in need thereof a therapeutically effective amount of a compound of Formulas I-1 or I-2, wherein said Formulas I-1 and I-2 are represented by:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof

wherein j is 0, 1 or 2;

wherein m is 0, 1, 2, 3 or 4;

wherein R2A and R2B are independently selected from the group consisting of hydrogen and hydrocarbyl;

wherein R9 and R10 are independently selected from the group consisting of hydrogen; hydrocarbyl; amino; and hydrocarbylamino;

wherein R5 is selected from the group consisting of hydrogen; hydrocarbyl, heterocyclyl; quaternary heterocyclyl; —OR9; —SR9; —S(O)R9; —SO2R9; and —SO3R9;

wherein when R5 is said cycloalkyl, aryl or heterocyclyl, said cycloalkyl, aryl or heterocyclyl are optionally substituted with —NH—X—R or —O—X—R;

wherein X is selected from the group consisting of —(C═O)s-alkyl-; —(C═O)s-alkyl-NH—; —(C═O)s-alkyl-O—; —(C═O)s-alkyl-(C═O)t; and a covalent bond, wherein s and t are independently 0 or 1;

wherein R is selected from the group consisting of monosaccharides, disaccharides, and polysaccharides, wherein said monosaccharides, disaccharides, and polysaccharides are optionally protected with one or more sugar protecting groups;

wherein, in each instance, said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein, in each instance, said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus and combinations thereof.

40. A method of treating gallstones or a condition associated therewith in a subject comprising administering to said subject in need thereof a therapeutically effective amount of a compound of Formulas I-1 or I-2 represented by:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof

wherein j is 0, 1 or 2;

wherein m is 0, 1, 2, 3 or 4;

wherein R2A and R2B are independently selected from the group consisting of hydrogen and hydrocarbyl;

wherein R9 and R10 are independently selected from the group consisting of hydrogen; hydrocarbyl; amino; and hydrocarbylamino;

wherein R5 is selected from the group consisting of hydrogen; hydrocarbyl, heterocyclyl; quaternary heterocyclyl; —OR9; —SR9; —S(O)R9; —SO2R9; and —SO3R9;

wherein when R5 is said cycloalkyl, aryl or heterocyclyl, said cycloalkyl, aryl or heterocyclyl are optionally substituted with —NH—X—R or —OX—R;

wherein X is selected from the group consisting of —(C═O)s-alkyl-; —(C═O)s-alkyl-NH—; —(C═O)s-alkyl-O—; —(C═O)s-alkyl-(C═O)t; and a covalent bond, wherein s and t are independently 0 or 1;

wherein R is selected from the group consisting of monosaccharides, disaccharides, and polysaccharides, wherein said monosaccharides, disaccharides, and polysaccharides are optionally protected with one or more sugar protecting groups;

wherein, in each instance, said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein, in each instance, said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus and combinations thereof.

41. The method of embodiment 39, wherein said subject is a mammal.

42. The method of embodiment 41, wherein said subject is a human.

43. The method of embodiment 40 wherein said subject is a mammal.

44. The method of embodiment 43, wherein said mammal is a human.

45. The method of embodiment 39, wherein said therapeutically effective amount is administered in a single dose or in multiple divided doses.

46. The method of embodiment 40, wherein said therapeutically effective amount is administered in a single dose or in multiple divided doses.

47. A method for treating a hyperlipidemic condition in a subject comprising administering to said subject in need thereof a therapeutically effective amount of a compound of Formulas I-17 or I-18 represented by:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof

wherein j is 0, 1 or 2;

wherein m is 0, 1, 2, 3 or 4;

wherein R2A and R2B are independently selected from the group consisting of hydrogen and hydrocarbyl;

wherein R9 and R10 are independently selected from the group consisting of hydrogen; hydrocarbyl; amino; and hydrocarbylamino;

wherein R5 is selected from the group consisting of hydrogen; hydrocarbyl, heterocyclyl; quaternary heterocyclyl; —OR9; —SR9; —S(O)R9; —SO2R9; and —SO3R9;

wherein when R5 is said cycloalkyl, aryl or heterocyclyl, said cycloalkyl, aryl or heterocyclyl are optionally substituted with —NH—X—R or —O—X—R;

wherein X is selected from the group consisting of —(C═O)s-alkyl-; —(C═O)s-alkyl-NH—; —(C═O)s-alkyl-O—; —(C═O)s-alkyl-(C═O)t; and a covalent bond, wherein s and t are independently 0 or 1;

wherein R is selected from the group consisting of monosaccharides, disaccharides, and polysaccharides, wherein said monosaccharides, disaccharides, and polysaccharides are optionally protected with one or more sugar protecting groups;

wherein, in each instance, said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein, in each instance, said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus and combinations thereof.

48. The method of embodiment 47 wherein said Formula I-17 comprises a member selected from the group consisting of I-21 and I-22 represented by:

52. The method of embodiment 51 where said Formula I-11 comprises a member selected from the group consisting of Formulas I-13 and I-16 represented by:

53. The method of embodiment 51 wherein said Formula I-12 comprises a member selected from the group consisting of Formulas I-14 and I-15 represented by:

54. The method of embodiments 47-53 wherein said R5 is a member selected from the group consisting of (1)-(69) and (70):

provided that when said R5 is (7), (17) or (24), then said R5A is a left end of said R5 and said R5B is a right end of said R5 or vice versa.

55. A method for treating gallstones or a condition associated therewith in a subject in need thereof, said method comprising administering a therapeutically effective amount of a compound of Formulas I-17 or I-18 represented by:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof

wherein j is 0, 1 or 2;

wherein m is 0, 1, 2, 3 or 4;

wherein R2A and R2B are independently selected from the group consisting of hydrogen and hydrocarbyl; wherein R3A, R3B, R5A, and R5B are independently selected from the group consisting of hydrogen, alkyl; cycloalkyl; alkenyl; alkynyl; heterocyclyl; quaternary heterocyclyl, oxo; aryl-R5; —OR9; —NR9R10; —SR9; —S(O)R9; —SO2R9; and —SO3R9;

wherein R9 and R10 are independently selected from the group consisting of hydrogen; hydrocarbyl; amino; and hydrocarbylamino;

wherein R5 is selected from the group consisting of hydrogen; hydrocarbyl, heterocyclyl; quaternary heterocyclyl; —OR9; —SR9; —S(O)R9; —SO2R9; and —SO3R9;

wherein when R5 is said cycloalkyl, aryl or heterocyclyl, said cycloalkyl, aryl or heterocyclyl are optionally substituted with —NH—X—R or —O—X—R;

wherein X is selected from the group consisting of —(C═O)s-alkyl-; —(C═O)s-alkyl-NH—; —(C═O)s-alkyl-O—; —(C═O)s-alkyl-(C═O)t; and a covalent bond, wherein s and t are independently 0 or 1;

wherein R is selected from the group consisting of monosaccharides, disaccharides, and polysaccharides, wherein said monosaccharides, disaccharides, and polysaccharides are optionally protected with one or more sugar protecting groups;

wherein, in each instance, said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein, in each instance, said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus and combinations thereof.

56. The method of embodiment 55 wherein said Formula I-17 comprises a member selected from the group consisting of I-21 and I-22 represented by:

wherein R9 and R10 are independently selected from the group consisting of hydrogen; hydrocarbyl; amino; and hydrocarbylamino;

wherein R5 is selected from the group consisting of hydrogen; hydrocarbyl; heterocyclyl; quaternary heterocyclyl; —OR9; —SR9; —S(O)R9; —SO2R9; and —SO3R9;

wherein when R5 is said cycloalkyl, aryl or heterocyclyl, said cycloalkyl, aryl or heterocyclyl are optionally substituted with —NH—X—R or —O—X—R;

wherein X is selected from the group consisting of —(C═O)s-alkyl-; —(C═O)s-alkyl-NH—;—(C═O)s-alkyl-O—; (C═O)s-alkyl-(C═O)t; and a covalent bond, wherein s and t are independently 0 or 1;

wherein R is selected from the group consisting of monosaccharides, disaccharides, and polysaccharides, wherein said monosaccharides, disaccharides, and polysaccharides are optionally protected with one or more sugar protecting groups;

wherein, in each instance, said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein, in each instance, said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus and combinations thereof,

wherein R9 and R10 are independently selected from the group consisting of hydrogen; hydrocarbyl; amino; and hydrocarbylamino;

wherein R5 is selected from the group consisting of hydrogen; hydrocarbyl; heterocyclyl; quaternary heterocyclyl; —OR9; —SR9; —S(O)R9; —SO2R9; and —SO3R9;

wherein when R5 is said cycloalkyl, aryl or heterocyclyl, said cycloalkyl, aryl or heterocyclyl are optionally substituted with —NH—X—R or —O—X—R;

wherein X is selected from the group consisting of —(C═O)s-alkyl-; —(C═O)s-alkyl-NH—; —(C═O)s-alkyl-O—; —(C═O)s-alkyl-(C═O)t; and a covalent bond, wherein s and t are independently 0 or 1;

wherein R is selected from the group consisting of monosaccharides, disaccharides, and polysaccharides, wherein said monosaccharides, disaccharides, and polysaccharides are optionally protected with one or more sugar protecting groups;

wherein, in each instance, said hydrocarbyl may be optionally substituted with one or more groups comprising one or more heteroatoms, and wherein, in each instance, said hydrocarbyl optionally may have one or more carbon atoms replaced by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus and combinations thereof,

72. The method of embodiment 70 wherein said R5 group is attached at least either at a meta position or at a para position of said phenyl ring attached to said 5-carbon on position of said benzothiepene of said Formulas I-21 or I-22.

73. The method of embodiment 66 wherein said compound of Formula I-2 is selected from the group consisting of Formulas I-3 and I-4 represented by:

wherein R2A, R2B, R3A, R3B, R5A, R5B, R6, m and j are as previously defined and said R5 is selected from the group consisting of (1)-(69) and (70):

provided that when said R5 is (7), (17) or (24), then said R5A is a left end of said R5 and said R5B is a right end of said R5 or vice versa.

74. The method of embodiment 73 wherein said Formula I-3 comprises a member selected from the group consisting of Formulas I-5 and I-6 represented by:

75. The method of embodiment 73 wherein said Formula I-4 comprises a member selected from the group consisting of Formulas I-7 and I-8 represented by:

93. The compound of embodiment 1 wherein said compound of Formula I-2 is selected from the group consisting of Formulas I-11 and I-12 represented by:

94. The method of embodiment 39 wherein said hyperlipidemic condition is hypercholesterolemia.

95. The method of embodiment 94 wherein said therapeutically effective amount is a daily dose from about 0.001 mg to about 10,000 mg.

96. The method of embodiment 95 wherein said daily dose is from about 0.005 mg to about 1,000 mg.

97. The method of embodiment 96 wherein said daily dose is from about 0.008 to about 100 mg.

98. The method of embodiment 97 wherein said daily dose is from about 0.05 mg to about 50 mg.

99. The method of embodiments 95-98 wherein said daily dose is administered as a single dose or in multiple divided doses.

100. The method of embodiment 40 wherein said therapeutically effective amount is a daily dose from about 0.001 mg to about 10,000 mg

101. The method of embodiment 100 wherein said daily dose is from about 0.005 mg to about 1,000 mg.

102. The method of embodiment 101 wherein said daily dose is from about 0.008 to about 100 mg.

103. The method of embodiment 102 wherein said daily dose is from about 0.05 mg to about 50 mg.

104. The method of embodiments 100-103 wherein said daily dose is administered as a single dose or in multiple divided doses.

105. The method of embodiment 95 wherein said daily dose is administered orally.

106. The method of embodiment 95 wherein said daily dose is administered parenterally.

107. The method of embodiment 95 wherein said daily dose is administered rectally.

108. The method of embodiment 107 wherein said daily dose is administered as a rectal dosage form comprising a suppository.

109. The method of embodiment 94 wherein said therapeutically effective amount is administered as a slow release dosage form.

110. The method of embodiment 109 wherein said slow release dosage form comprises an implant.

111. The method of embodiment 105 wherein said daily dose is administered in the form of an oral dosage form selected from the group consisting of a tablet, a capsule, a powder, a solution, a suspension, an emulsion, and a syrup.

112. The method of embodiment 111 wherein said solution comprises a syrup.

113. The method of embodiment 111 wherein said oral dosage form comprises a sublingual tablet, an effervescent tablet, or a slow release tablet.

114. The method of embodiment 106 wherein said parenteral dosage form is selected from the group consisting of an intramuscular injection, an intravenous injection, and a subcutaneous injection.

115. The method of embodiment 95 wherein said daily dose is administered topically.

116. The method of embodiment 100 wherein said daily dose is administered parenterally.

117. The method of embodiment 100 wherein said daily dose is administered rectally or vaginally.

118. The method of embodiment 117 wherein said daily dose is administered as a rectal dosage form or a vaginal dosage form comprising a suppository.

119. The method of embodiment 100 wherein said daily dose is administered as a slow release dosage form.

120. The method of embodiment 119 wherein said slow release dosage form comprises an implant.

121. The method of embodiment 100 wherein said daily dose is administered in the form of an oral dosage form selected from the group consisting of a tablet, a capsule, a powder, a solution, a suspension, and an emulsion.

122. The method of embodiment 121 wherein said solution comprises a syrup.

123. The method of embodiment 121 wherein said tablet comprises a sublingual tablet, an effervescent tablet, or a slow release tablet.

124. The method of embodiment 116 wherein said parenteral dosage form is selected from the group consisting of an intramuscular injection, an intravenous injection, and a subcutaneous injection.

125. The method of embodiment 100 wherein said daily dose is administered topically.

126. The method of embodiment 125 wherein said daily dose is administered in the form of a topical dosage form selected from the group consisting of a lotion, a cream, a suspension, an emulsion, a paste, and a solution.

127. The method of embodiment 115 wherein said daily dose is administered in the form of a topical dosage form selected from the group consisting of a lotion, a cream, a suspension, an emulsion, a paste, and a solution.

128. A pharmaceutical composition comprising a compound of Formula I-1 or I-2 of embodiment 1 and a pharmaceutically acceptable carrier.

140. The pharmaceutical composition of embodiment 128 wherein said compound of Formula I-2 is selected from the group consisting of Formulas I-11 and I-12 represented by:

141. The pharmaceutical composition of embodiment 128 provided in a coated dosage form, said coated dosage form having a coating of cellulose acetate phthalate, polyvinylacetate pththalate, hydroxypropylmethyl cellulose phthalate, or an anionic polymer of methacrylic acid and methacrylic acid methyl ester.

142. The compound of embodiment 1 provided in a coated dosage form, said coated dosage form having a coating of cellulose acetate phthalate, polyvinylacetate pththalate, hydroxypropylmethyl cellulose phthalate, or an anionic polymer of methacrylic acid and methacrylic acid methyl ester.

143. The pharmaceutical composition of embodiment 128 provided in a dosage form selected from the group consisting of a tablet, a capsule, a suspension, an emulsion, a solution, a cream, a paste, a lotion, a suppository, or a powder.

144. The pharmaceutical composition of embodiment 128 in a dosage form selected from the group consisting of a sublingual tablet, an effervescent tablet, and a coated tablet.

145. The pharmaceutical composition of embodiment 128 provided in a dosage form comprising a slow release dosage form.

146. The pharmaceutical composition of embodiment 145 wherein said slow release dosage form is selected from the group consisting of an implant or a coated tablet.

147. The pharmaceutical composition of embodiment 146 wherein said solution, said suspension or said emulsion are suitable for parenteral administration to said subject.

148. The pharmaceutical composition of embodiment 143 wherein said solution comprises a syrup.

149. The pharmaceutical composition of embodiment 128 provided in a dosage form comprising a dispersion.

150. The compound of embodiment 1 provided in a dosage form selected from the group consisting of a tablet, a capsule, a suspension, an emulsion, a solution, a cream, a paste, a lotion, a suppository, and a powder.

EXAMPLES OF SYNTHETIC PROCEDURES

The following examples use a numbering scheme for referring to the various compounds depicted below that may be different from the numbering scheme that is used in the earlier part of this patent application.

Preparation 12-Ethyl-2-(mesyloxymethyl)hexanal (1)

To a cold (10° C.) solution of 12.6 g (0.11 mole) of methanesulfonyl chloride and 10.3 g (0.13 mole) of triethylamine was added dropwise 15.8 g of 2-ethyl-2-(hydroxymethyl)hexanal, prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), while maintaining the reaction temperature below 30° C. The reaction mixture was stirred at room temperature for 18 h, quenched with dilute HCl and extracted with methylene chloride. The methylene chloride extract was dried over MgSO4 and concentrated in vacuo to give 24.4 g of brown oil.

Preparation 22-((2-Benzoylphenylthio)methyl-2-ethylhexanal (2)

A mixture of 31 g (0.144 mol) of 2-mercaptobenzophenone, prepared according to the procedure described in WO 93/16055, 24.4 g (0.1 mole) of 2-ethyl-2-(mesyloxymethyl)-hexanal 1, 14.8 g (0.146 mole) of triethylamine, and 80 mL of 2-methoxyethyl ether was held at reflux for 24 h. The reaction mixture was poured into 3N HCl and extracted with 300 mL of methylene chloride. The methylene chloride layer was washed with 300 mL of 10% NaOH, dried over MgSO4 and concentrated in vacuo to remove 2-methoxyethyl ether. The residue was purified by HPLC (10% EtOAc-hexane) to give 20.5 g (58%) of 2 as an oil.

A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl3 and 80 mL of anhydrous ethylene glycol dimethyl ether (DME) was held at reflux for 2 h. The reaction mixture was cooled to 5° C. To the reaction mixture was added dropwise a solution of 3.54 g (0.01 mole) of 2 in 30 mL of DME in 40 min. The reaction mnixture was stirred at room temperature for 16 h and then was held at reflux for 2 h and cooled before being poured into brine. The organic was extract into methylene chloride. The methylene chloride extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by HPLC (hexane) to give 1.7 g (43%) of 3 as an oil in the first fraction. The second fraction was discarded and the third fraction was further purified by HPLC (hexane) to give 0.07 g (2%) of 4a in the earlier fraction and 0.1 g (3%) of 4b in the later fraction.

To a solution of 1.2 g (3.5 mmole) of 50-60% MCPBA in 20 mL of methylene chloride was added 0.59 g (1.75 mmole) of a mixture of 4a and 4b in 10 mL of methylene chloride. The reaction mixture was stirred for 20 h. An additional 1.2 g (1.75 mmole) of 50-60% MAPBA was added and the reaction mixture was stirred for an additional 3 h then was triturated with 50 mL of 10% NaOH. The insoluble solid was filtered. The methylene chloride layer of the filtrate was washed with brine, dried over MgSO4, and concentrated in vacuo. The residual syrup was purified by HPLC (5% EtOAc-hexane) to give 0.2 g (30%) of 5a as an oil in the first fraction and 0.17 g (26%) of 5b as an oil in the second fraction.

To a solution of 0.22 g (0.59 mmole) of 5b in 10 mL of ethanol was added 0.24 g (6.4 mmole) of sodium borohydride. The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo to remove ethanol. The residue was triturated with water and extracted with methylene chloride. The methylene chloride extract was dried over MgSO4 and concentrated in vacuo to give 0.2 g of syrup. In a separate experiment, 0.45 g of 5a was treated with 0.44 g of sodium borohydride in 10 mL of ethanol and was worked up as described above to give 0.5 g of syrup which was identical to the 0.2 g of syrup obtained above. These two materials were combined and purified by HPLC using 10% EtOAc-hexane as eluant. The first fraction was 0.18 g (27%) of 6a as a syrup. The second fraction was 0.2 g (30%) of 6b also as a syrup. The column was then eluted with 20% EtOAc-hexane to give 0.077 g (11%) of 6c in the third fraction as a solid. Recrystallization from hexane gave a solid, mp 179-181° C. Finally, the column was eluted with 30% EtOAc-hexane to give 0.08 g (12%) of 6d in the fourth fraction as a solid. Recrystallization from hexane gave a solid, mp 160-161° C.

B. Conversion of 6a to 6c and 6d With NaOH and PTC

To a solution of 0.29 g (0.78 mmole) of 6a in 10 mL CH2Cl2, was added 9 g of 40% NaOH. The reaction mixture was stirred for 0.5 h at room temperature and was added one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst (PTC). The mixture was stirred for 0.5 h at room temperature before being treated with 25 mL of ice-crystals then was extracted with CH2Cl2 (3×10 ml), dried over MgSO4 and concentrated in vacuo to recover 0.17 g of a colorless film. The components of this mixture were separated using an HPLC and eluted with EtOAc-hexane to give 12.8 mg (4%) of 2-(2-benzylphenylsulfonylmethyl)-2-ethylhexenal in the first fraction, 30.9 mg (11%) of 6c in the second fraction and 90.0 mg (31%) of 6d in the third fraction.

Oxidation of 6a to 5b

To a solution of 0.20 g (0.52 mmole) of 6a in 5 mL of CH2Cl2 was added 0.23 g (1.0 mmole) of pyridinium chlorochromate. The reaction mixture was stirred for 2 h then was treated with additional 0.23 g of pyridinium chlorochromate and stirred overnight. The dark reaction mixture was poured into a ceramic filterfrit containing silica gel and was eluted with CH2Cl2. The filtrate was concentrated in vacuo to recover 167 mg (87%) of 5b as a colorless oil.

To a solution of 5.13 g (15.9 mmole) of 3 in 50 mL of CH2Cl2 was added 10 g (31.9 mmole)of 50-60% MCPBA (m-chloroperoxybenzoic acid) portionwise causing a mild reflux and formation of a white solid. The reaction mixture was allowed to stir overnight under N2 and was triturated with 25 mL of water followed by 50 mL of 10% NaOH solution. The organic was extracted into CH2Cl2 (4×20 mL). The CH2Cl2 extract was dried over MgSO4 and evaporated to dryness to recover 4.9 g (87%) of an opaque viscous oil.

To 1.3 g (4.03 mole) of 3 in 25 mL of CHCl3 was added portionwise 5 g (14.1 mmole) of 50-60% MCPBA causing a mild exotherm. The reaction mixture was stirred under N2 overnight and was then held at reflux for 3 h. The insoluble white slurry was filtered. The filtrate was extracted with 10% potassium carbonate (3×50 mL), once with brine, dried over MgSO4, and concentrated in vacuo to give 1.37 g of a light yellow oil. Purification by HPLC gave 0.65 g of crystalline product. This product is a mixture of two isomers. Trituration of this crystalline product in hexane recovered 141.7 mg (10%) of a white crystalline product. This isomer was characterized by NMR and mass spectra to be the (1aα,2β,8bα) isomer 8a. The hexane filtrate was concentrated in vacuo to give 206 mg of white film which is a mixture of 30% 8a and 70% 8b by 1H NMR.

A mixture of 0.15 g (0.4 mmole) of a 3:7 mixture of 8a and 8b was dissolved in 15 ml MeOH in a 3 oz. Fisher/Porter vessel, then was added 0.1 g of 10% Pd/C catalyst. This mixture was hydrogenated at 70 psi H2 for 5 h and filtered. The filtrate was evaporated to dryness in vacuo to recover 0.117 g of a colorless oil. This material was purified by HPLC eluting with EtOAc-hexane. The first fraction was 4.2 mg (3%) of 9b. The second fraction, 5.0 mg (4%), was a 50/50 mixture of 9a and 9b. The third fraction was 8.8 mg (6%) of 6a. The fourth fraction was 25.5 mg (18%) of 6b. The fifth fraction was 9.6 mg (7%) of a mixture of 6b and a product believed to be 3-butyl-3-ethyl-4,5-dihydroxy-5-phenyl-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide based on mass spectrum. The sixth fraction was 7.5 mg (5%) of a mixture of 6d and one of the isomers of 10, 10a

Example 7

In another experiment, a product (3.7 g) from epoxidation of 3 with excess MCPBA in refluxing CHCl3 under air was hydrogenated in 100 mL of methanol using 1 g of 10% Pd/C catalyst and 70 psi hydrogen. The product was purified by HPLC to give 0.9 g (25%) of 9b, 0.45 g (13%) of 9a, 0.27 g (7%) of 6a, 0.51 g (14%) of 6b, 0.02 g (1%) of 6c, 0.06 g (2%) of one isomer of 10, 10a and 0.03 g (1%) of another isomer of 10, 10b.

Example 82-((2-Benzoylphenylthio)methyl)butyraldehyde (11)

To an ice bath cooled solution of 9.76 g (0.116 mole) of 2-ethylacrolein in 40 mL of dry THF was added 24.6 g (0.116 mole) of 2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128 mole) of triethylamine. The reaction mixture was stirred at room temperature for 3 days, diluted with ether, and was washed successively with dilute HCl, brine, and 1 M potassium carbonate. The ether layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc-hexane) to give 22 g (64%) of 11 in the second fraction. An attempt to further purify this material by kugelrohr distillation at 0.5 torr (160-190° C.) gave a fraction (12.2 g) which contained starting material indicating a reversed reaction during distillation. This material was dissolved in ether (100 mL) and was washed with 50 mL of 1 M potassium carbonate three times to give 6.0 g of a syrup which was purified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11.

Example 93-Ethyl-5-phenyl-2,3-dihydrobenzothiepine (12)

To a mixture of 2.61 g (0.04 mole) of zinc dust and 60 mL of DME was added 7.5 g (0.048 mole) of TiCl3. The reaction mixture was held at reflux for 2 h. A solution of 2.98 g (0.01 mole) of 11 was added dropwise in 1 h. The reaction mixture was held at reflux for 18 h, cooled and poured into water. The organic was extracted into ether. The ether layer was washed with brine and filtered through Celite. The filtrate was dried over MgSO4 and concentrated. The residual oil (2.5 g) was purified by HPLC to give 2.06 g (77%) of 12 as an oil in the second fraction.

To a solution of 1.5 g (5.64 mmole) of 12 in 25 ml of CHCl3 was added 6.8 g (19.4 mmole) of 50-60% MCPB portionwise causing an exotherm and formation of a white solid. The mixture was stirred at room temperature overnight diluted with 100 ml methylene chloride and washed successively with 10% K2CO3 (4×50 ml), water (twice with 25 ml) and brine. The organic layer was then dried over MgSO4 and evaporated to dryness to recover 1.47 g of an off white solid. 1H NMR indicated that only one isomer is present. This solid was slurried in 200 ml of warm Et2O and filtered to give 0.82 g (46%) of 13 as a white solid, mp 185-186.5° C.

A mixture of 0.5 g (1.6 mole) of 13, 50 ml of acetic acid and 0.5 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 4 h. The crude reaction slurry was filtered and the filtrate was stirred with 150 ml of a saturated NaHCO3 solution followed by 89 g of NaHCO3 powder portionwise to neutralize the rest of acetic acid. The mixture was extracted with methylene chloride (4×25 ml), then the organic layer was dried over MgSO4 and concentrated in vacuo to give 0.44 g (87%) of a voluminous white solid which was purified by HPLC (EtOAc-Hexane) to give 26.8 mg (6%) of 15 in the first fraction, 272 mg (54%) of 14a as a solid, mp 142-143.5° C., in the second fraction, and 35 mg (7%) of impure 14b in the third fraction.

Example 122-Ethyl-2-((2-hydroxymethylphenyl)thiomethyl)hexenal (16)

A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl alcohol, 6.4 g (0.032 mole) of 1, 3.6 g (0.036 mole) of triethylamine and 25 mL of 2-methoxyethyl ether was held at reflux for 7 h. Additional 1.1 g of mercaptobenzyl alcohol and 0.72 g of triethylamine was added to the reaction mixture and the mixture was held at reflux for additional 16 h. The reaction mixture was cooled and poured into 6N HCl and extracted with methylene chloride. The methylene chloride extract was washed twice with 10% NaOH, dried over MgSO4 and concentrated in vacuo to give 9.6 g of residue. Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%) of 16 as an oil.

Example 132-Ethyl-2-((2-formylphenyl)thiomethyl)hexenal (17)

A mixture of 3.7 g of 16, 5.6 g (0.026 mole) of pyridinium chlorochromate, 2 g of Celite and 30 mL of methylene chloride was stirred for 18 h and filtered through a bed of silica gel. The silica gel was eluted with methylene chloride. The combined methylene chloride eluant was purified by HPLC (20% ETOAc-hexane) to give 2.4 g (66%) of an oil.

Example 143-Butyl-3-ethyl-2,3-dihydrobenzothiepine (18)

A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl3, and 50 mL of DME was held at reflux for 2 h and cooled to room temperature. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mL of DME in 10 min. The reaction mixture was stirred at room temperature for 2 h and held at reflux for 1 h then was let standing at room temperature over weekend. The reaction mixture was poured into dilute HCl and was stirred with methylene chloride. The methylene chloride-water mixture was filtered through Celite. The methylene chloride layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give 3.0 g of a residue. Purification by HPLC gave 0.41 g (20%) of 18 as an oil in the early fraction.

To a solution of 0.4 g of 0.4 g (1.6 mmole) of 18 in 30 mL of methylene chloride was added 2.2 g (3.2 mmole) of 50-60% MCPBA. The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in 30 mL of CHCl3 and was held at reflux for 18 h under N2. The reaction mixture was stirred with 100 mL of 10% NaOH and 5 g of sodium sulfite. The methylene chloride layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by HPLC (20% EtOAc-hexane) to give a third fraction which was further purified by HPLC (10% EtOAc-hexane) to give 0.12 g of syrup in the first fraction. Recrystallization from hexane gave 0.08 g (17%) of 19a, mp 89.5-105.5° C. The mother liquor from the first fraction was combined with the second fraction and was further purified by HPLC to give additional 19a in the first fraction and 60 mg of 19b in the second fraction. Crystallization from hexane gave 56 mg of a white solid.

A mixture of 25 mg (0.085 mmole) of 19b, 0.27 g (2.7 mmole) of thiophenol, 0.37 g (2.7 mmole) of potassium carbonate, and 4 mL of DMF was stirred at room temperature under N2 for 19 h. The reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride layer was washed successively with 10% NaOH and brine, dried over MgSO4, and concentrated in vacuo to give 0.19 g of semisolid which contain substantial amounts of diphenyl disulfide. This material was purified by HPLC (5% EtOAc-hexane) to remove diphenyl disulfide in the first fraction. The column was then eluted with 20% EtOAc-hexane to give 17 mg of a first fraction, 4 mg of a second fraction and 11 mg of a third fraction which were three different isomers of 21, i.e. 21a, 21b, and 21c, respectively, by 1H NMR and mass spectra.

To a solution of 9.0 g (0.025 mole) of compound 2 in 100 ml of methylene chloride was added 14.6 g (0.025 mol) of 50-60% MCPBA portionwise. The reaction mixture was stirred at room temperature for 64 h then was stirred with 200 ml of 1 M potassium carbonate and filtered through Celite. The methylene chloride layer was washed twice with 300 ml of 1 M potassium carbonate, once with 10% sodium hydroxide and once with brine. The insoluble solid formed during washing was removed by filtration through Celite. The methylene chloride solution was dried and concentrated in vacuo to give 9.2 g (95%) of semisolid. A portion (2.6 g) of this solid was purified by HPLC(10% ethyl acetate-hexane) to give 1.9 g of crystals, mp 135-136° C.

Step 2. 2-((2-Benzylphenylsulfonyl)methyl)-2-ethylhexanal (45)

A solution of 50 g (0.13 mole) of crude 44 in 250 ml of methylene chloride was divided in two portions and charged to two Fisher-Porter bottles. To each bottle was charged 125 ml of methanol and 5 g of 10% Pd/C. The bottles were pressurized with 70 psi of hydrogen and the reaction mixture was stirred at room temperature for 7 h before being charged with an additional 5 g of 10% Pd/C. The reaction mixture was again hydrogenated with 70 psi of hydrogen for 7 h. This procedure was repeated one more time but only 1 g of Pd/C was charged to the reaction mixture. The combined reaction mixture was filtered and concentrated in vacuo to give 46.8 g of 45 as brown oil.

To a solution of 27.3 g (73.4 mmole) of 45 in 300 ml of anhydrous THF cooled to 2° C. with an ice bath was added 9.7 g (73.4 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred for 20 min, quenched with 300 ml of 10% HCl and extracted with methylene chloride. The methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to give 24.7 g of yellow oil. Purification by HPLC (ethyl acetate-hexane) yielded 9.4 g of recovered 45 in the first fraction, 5.5 g (20%) of 6c in the second fraction and 6.5 g (24%) of 6d in the third fraction.

B. Preparation from 2-Hydroxydiphenylmethane

Step 1. 2-Mercaptodiphenylmethane (46)

To a 500 ml flask was charged 16 g (0.33 mol) of 60% sodium hydride oil dispersion. The sodium hydride was washed twice with 50 ml of hexane. To the reaction flask was charged 100 ml of DMF. To this mixture was added a solution of 55.2 g (0.3 mol) of 2-hydroxydiphenylmethane in 200 ml of DMF in 1 h while temperature was maintained below 30° C. by an ice-water bath. After complete addition of the reagent, the mixture was stirred at room temperature for 30 min then cooled with an ice bath. To the reaction mixture was added 49.4 g (0.4 mole) of dimethyl thiocarbamoyl chloride at once. The ice bath was removed and the reaction mixture was stirred at room temperature for 18 h before being poured into 300 ml of water. The organic was extracted into 500 ml of toluene. The toluene layer was washed successively with 10% sodium hydroxide and brine and was concentrated in vacuo to give 78.6 g of a yellow oil which was 95% pure dimethyl O-2-benzylphenyl thiocarbamate. This oil was heated at 280-300° C. in a kugelrohhr pot under house vacuum for 30 min. The residue was kugelrohr distilled at 1 torr (180-280° C.). The distillate (56.3 g) was crystallized from methanol to give 37.3 g (46%) of the rearranged product dimethyl S-2-benzylphenyl thiocarbamate as a yellow solid. A mixture of 57 g (0.21 mole) of this yellow solid, 30 g of potassium hydroxide and 150 ml of methanol was stirred overnight then was concentrated in vacuo. The residue was diluted with 200 ml of water and extracted with ether. The aqueous layer was made acidic with concentrate HCl, The oily suspension was extracted into ether. The ether extract was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from hexane to give 37.1 g (88%) of 2-mercaptodiphenylmethane as a yellow solid.

Step 2. 2-((2-Benzylphenylthio)methyl)-2-ethythexanal (47)

A mixture of 60 g (03 mole) of yellow solid from step 1, 70 g (0.3 mole) of compound 1 from preparation 1, 32.4 g (0.32 mole) of triethylarnine, 120 ml of 2-methoxyethyl ether was held at reflux for 6 hr and concentrated in vacuo. The residue was triturated with 500 ml of water and 30 ml of concentrate HCl. The organic was extracted into 400 ml of ether. The ether layer was washed successively with brine, 10% sodium hydroxide and brine and was dried over magnesium sulfate and concentrated in vacuo. The residue (98.3 g) was purified by HPLC with 2-5% ethyl acetate-hexane as eluent to give 2-((2-benzylphenylthio)methyl)-2-ethylhexanal 47 as a yellow syrup.

Step 3. 2-((2-Benzylphenylsulfonyl)methyl)-2-ethylhexanal (45)

To a solution of 72.8 g (0.21 mole) of yellow syrup from step 2 in 1 liter of methylene chloride cooled to 10° C. was added 132 g of 50-60% MCPBA in 40 min. The reaction mixture was stirred for 2 h. An additional 13 g of 50-60% MCPBA was added to the reaction mixture. The reaction mixture was stirred for 2 h and filtered through Celite. The methylene chloride solution was washed twice with 1 liter of 1 M potassium carbonate then with 1 liter of brine. The methylene chloride layer was dried over magnesium sulfate and concentrated to 76g of 2-((2-benzylphenylsulfonyl)methyl)-2-ethylhexanal 45 as a syrup.

2-Hydroxy-4-methoxybenzophenone was converted to the dimethyl O-2-benzoyphenyl thiocarbamate by methods previously described in example 18. The product can be isolated by recrystallization from ethanol. Using this improved isolation procedure no chromatography was needed. The thermal rearrangement was performed by reacting the thiocarbamate(5 g) in diphenyl ether at 260° C. as previously described. The improved isolation procedure which avoided a chromatography step was described below.

The crude pyrolysis product was then heated at 65° C. in 100 ml of methanol and 100 ml of THF in the presence of 3.5 g of KOH for 4 h. After removing THF and methanol by rotary evaporation the solution was extracted with 5% NaOH and ether. The base layer was acidified and extracted with ether to obtain a 2.9 g of crude thiophenol product. The product was further purified by titrating the desired mercaptan into base with limited KOH. After acidification and extraction with ether pure 2-mercapto-4-methoxybenzophenone (2.3 g) was isolated.

2-mercapto-4-methoxybenzophenone can readily be converted to the 2-(2-benzoyl-4-methoxyphenylthio)methyl)-2-ethylhexanal (22) by reaction with 2-ethyl-2-(mesyloxymethyl)hexanal (1) as previously described.

A 3-neck flask equipped with a powder addition funnel, thermocouple and nitrogen bubbler was charged with 19.8 g (0.05 mole) of sulfone 24 in 100 ml dry THF. The reaction was cooled to −1.6° C. internal temperature by means of ice/salt bath. Slowly add 5.61 g (0.05 mole) of potassium t-butoxide by means of the powder addition funnel. The resulting light yellow solution was maintained at −1.6° C. After 30 min reaction 400 ml of cold ether was added and this solution was extracted with cold 10% HCl. The acid layer was extracted with 300 ml of methylene chloride. The organic layers were combined and dried over magnesium sulfate and after filtration stripped to dryness to obtain 19.9 g of product. 1H nmr and glpc indicated a 96% conversion to a 50/50 mixture of 25 and 26. The only other observable compound was 4% starting sulfone 24.

The product was then dissolved in 250 ml of 90/10 hexane/ethyl acetate by warming to 50° C. The solution was allowed to cool to room temperature and in this way pure 26 can be isolated. The crystallization can be enhanced by addition of a seed crystal of 26. After 2 crystallizations the mother liquor which was now 85.4% 25 and has a dry weight of 8.7 g. This material was dissolved in 100 ml of 90/10 hexane/ethyl acetate and 10 ml of pure ethyl acetate at 40° C. Pure 25 can be isolated by seeding this solution with a seed crystal of 25 after storing it overnight at 0° C.

In a 25 ml round bottomed flask, 1 g of 26(2.5 mmoles) and 10 ml methylene chloride were cooled to −78° C. with stirring. Next 0.7 ml of boron tribromide(7.5 mmole) was added via syringe. The reaction was allowed to slowly warm to room temperature and stirred for 6 h. The reaction was then diluted with 50 ml methylene chloride and washed with saturated NaCl and then water. The organic layer was dried over magnesium sulfate. The product (0.88 g)27 was characterized by NMR and mass spectra.

Example 21General Alkylation of Phenol 27

A 25 ml flask was charged with 0.15 g of 27(0.38 mmole), 5 ml anhydrous DMF, 54 mg of potassium carbonate(0.38 mmole) and 140 mg ethyl iodide (0.9 mmole). The reaction was stirred at room temperature overnight. The reaction was diluted with 50 ml ethyl ether and washed with water (25 ml) then 5% NaOH (20 ml) and then sat. NaCl. After stripping off the solvent the ethoxylated product 28 was obtained in high yield. The product was characterized by NMR and mass spectra.

This same procedure was used to prepare products listed in table 1 from the corresponding iodides or bromides. For higher boiling alkyl iodides and bromides only one equivalent of the alkyl halide was used.

Under nitrogen, a 3 neck flask was charged with 45 g (0.172 mole) of 2-chloro-5-nitrobenzophenone in 345 ml methylene chloride and the solution was cooled to ice/water temperature. By means of an additional funnel, 150 g ( 0.172 mole) of trifluoromethane sulfonic acid in 345 ml methylene chloride was added slowly. Next 30 g of triethylsilane (0.172 mole) in 345 ml methylene chloride was added dropwise to the chilled solution. Both addition steps(trifluoromethane sulfonic acid and triethylsilane)were repeated. After the additions were completed the reaction was allowed to slowly warm up to room temperature and stirred for 12 h under nitrogen. The reaction mixture was then poured into a chilled stirred solution of 1600 ml of saturated sodium bicarbonate. Gas evolution occurred. Poured into a 4 liter separatory funnel and separated layers. The methylene chloride layer was isolated and combined with two 500 ml methylene chloride extractions of the aqueous layer. The methylene chloride solution was dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from hexane to give 39 g product. Structure 32 was confirmed by mass spectra and proton and carbon NMR.

The 2-chloro-5-nitrodiphenylmethane product 32 (40 g, 0.156 mole) from above was placed in a 2 liter 2 neck flask with water condenser. Next 150 ml DMSO and 7.18 g (0.156 mole) of lithium sulfide was added and the solution was stirred at 75° C. for 12 h. The reaction was cooled to room temperature and then 51.7 g of mesylate IV was added in 90 ml DMSO. The reaction mixture was heated to 80° C. under nitrogen. After 12 h monitored by TLC and added more mysylate if necessary. Continued the reaction until the reaction was completed. Next the reaction mixture was slowly poured into a 1900 ml of 5% acetic aqueous solution with stirring, extracted with 4×700 ml of ether, and dried over MgSO4. After removal of ether, 82.7 g of product was isolated. The material can be further purified by silica gel chromatography using 95% hexane and 5% ethyl acetate. If pure mysylate was used in this step there was no need for further purification. The product 33 was characterized by mass spectra and NMR.

Step 3. Oxidation of the Nitro Product 33 to the Sulfone 2-((2-Benzyl-4-nitrophenylsulfonyl)methyl)-2-ethylhexanal (34)

The procedure used to oxidize the sulfide 33 to the sulfone 34 has been previously described.

A 15 g sample of 34 was dissolved in 230 ml of ethanol and placed in a 500 ml rb flask under nitrogen. Next 1.5 g of 10 wt. % Pd/C was added and hydrogen gas was bubbled through the solution at room temperature until the nitro substrate 34 was consumed. The reaction could be readily monitored by silica gel TLC using 80/20 hexane/EtOAc. Product 35 was isolated by filtering off the Pd/C and then stripping off the EtOH solvent. The product was characterized by NMR and mass spectra.

The product was further purified by column chromatography using 90/10 hexanelethyl acetate and then 70/30 hexane/ethyl acetate. The product 36 was obtained (4.12 g) which appeared to be mainly the di-t-butoxycarbonyl) derivatives by proton NMR.

A 250ml 3-neck round bottomed flask was charged with 4 g of 36 (6.8 mmoles), and 100 ml of anhydrous THF and cooled to −78° C. under a nitrogen atmosphere. Slowly add 2.29 g potassium tert-butoxide(20.4 mmoles) with stirring and maintaining a −78° C. reaction temperature. After 1 h at −78° C. the addition of base was completed and the temperature was brought to −10° C. by means of a ice/salt bath. After 3 h at −10° C., only trace 36 remained by TLC. Next add 35 ml of deionized water to the reaction mixture at −10° C. and stirred for 5 min. Stripped off most of the THF and added to separatory funnel and extracted with ether until all of the organic was removed from the water phase. The combined ether phases were washed with saturated NaCl and then dried over sodium sulfate. The only products by TLC and NMR were the two BOC protected isomers of 37 and 38. The isomers were separated by silica gel chromatography using 85% hexane and 15% ethyl acetate; BOC-37 (0.71 g) and BOC-38 (0.78 g).

Next the BOC protecting group was removed by reacting 0.87 g of BOC-38 (1.78 mmoles) with 8.7 ml of 4 M HCl (34.8 mmoles)in dioxane for 30 min. Next added 4.74 g of sodium acetate (34.8 mmoles) to the reaction mixture and 16.5 ml ether and stirred until clear. After transferring to a separatory funnel extracted with ether and water and then dried the ether layer with sodium sulfate. After removing the ether, 0.665 g of 38 was isolated. Isomer 37 could be obtained in a similar procedure.

In a Fischer porter bottle weighed out 0.5 g of 34 (1.2 mmoles) and dissolved in 3.8 ml of ethanol under nitrogen. Next added 0.1 g of Pd/C and 3.8 ml of hexanal. Seal and pressure to 50 psi of hydrogen gas. Stirred for 48 h. After filtering off the catalyst and removing the solvent by rotary evaporation 39 was isolated by column chromatography (0.16 g) using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexane/ethyl acetate. The product was characterized by NMR and mass spectra.

A 2-neck, 25 ml round bottomed flask with stir bar was charged with 0.158 g 39 (0.335 mmole) and 5 ml anhydrous THF under nitrogen. Cool to −10° C. by means of a salt/water bath. Slowly add 0.113 g of potassium tert butoxide (0.335 mmole). After 15 min at −10° C. all of the starting material was consumed by TLC and only the two isomers 40 and 41 were observed. Next added 5 ml of chilled 10% HCl and stirred at −10° C. for 5 min. Transferred to a separatory fiunel and extract with ether. Dried over sodium sulfate. Proton NMR of the dried product (0.143 g) indicated only the presence of the two isomers 40 and 41. The two isomers were separated by silica gel chromatography using 90/10 hexane ethyl acetate and gradually increasing the mobile phase to 70/30 hexanelethyl acetate. 40 (53.2 mg); 41(58.9 mg).

Example 24Quaternization of Amine Substrates 40 and 41

Amine products such as 40 and 41 can be readily alkylated to quaternary salts by reaction with alkyl halides. For example 40 in DMF with 5 equivalents of methyl iodide in the presence of 2,6 dimethyl lutidine produces the dimethylhexylamino quaternary salt.

In a 25 ml round bottomed flask 0.5 g (1.3 mmole) of 6d, 0.67 g of mercuric triflate were dissolved in 20 ml of dry methylene chloride with stirring. Next 0.34 g of Iodine was added and the solution was stirred at room temperature for 30 h.

Reaction of 66.2 g of 4-methoxythiophenol with 360 ml of 2.5 N n-butyllithium, 105 g of tetramethylethylenediamine and 66.7 g of benzonitrile in 600 ml cyclohexane according to the procedure in WO 93/16055 gave 73.2 g of brown oil which was kugelrohr distilled to remove 4-methoxythiophenol and gave 43.86 g of crude 50 in the pot residue.

Step 2. 2-((2-Benzoyl-4-methoxyphenylthio)methyl-2-ethylhexanal (51)

Reaction of 10 g (0.04 mole) of crude 50 with 4.8 g (0.02 mole)of mesylate 1 and 3.2 ml (0.23 mole) of triethylamine in 50 ml of diglyme according to the procedure for the preparation of 2 gave 10.5 g of crude product which was purified by HPLC (5% ethyl acetate-hexane) to give 1.7 g (22%) of 51.

A solution of 1.2 g (3.1 mmoles) of 51 in 25 ml of methylene chloride was reacted with 2.0 g (6.2 mmoles) of 50-60% MCPBA according to the procedure of step 2 of procedure A in example 18 gave 1.16 g (90%) of 52 as a yellow oil.

A solution of 1.1 g of 53, 0.36 g of potassium t-butoxide and 25 ml of anhydrous THF was held at reflux for 2 h and worked up as in step 4 of procedure A of example 18 to give 1.07 g of a crude product which was purified by HPLC to give 40 mg (4%) of 48 as crystals, mp 153-154° C. and 90 mg (8%) of 49 as solid, mp 136-140° C.

To a cold (0° C.) mixture of 100 g (0.891 mole) of cyclohexanecarboxaldehyde, 76.5 g of 37% of formaldehyde in 225 ml of methanol was added dropwise 90 ml of 1 N Sodium hydroxide in 1 h. The reaction mixture was stirred at room temperature over 48 then was evaporated to remove methanol. The reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 75 g (59.7%) of thick oil. Proton NMR and mass spectra were consistent with the product.

Step 2. 1-(Mesyloxymethyl)cyclohexanecarboxaldehyde (55)

To a cold (0° C.) mixture of alcohol 54(75 g, 0.54 mole) and 65.29 g (0.57 mole) of methanesulfonyl chloride in 80 ml of methylene chloride was added a solution of pyridine (47.96 g, 0.57 mole) in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 h then quenched with water, acidified with conc. HCl and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 91.63 g (77.8%) of thick oil. Proton NMR and mass spectra were consistent with the product.

Step 3. 1-((2-Benzoylphenylthio)methyl)cyclohexanecarboxaldehyde (56)

A mixture of 69 g (0.303 mole) of 2-mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55, 32 g of triethylamine, and 150 ml of diglyme was stirred and held at reflux for 24 h. The mixture was cooled, poured into dil. HCl and extracted with methylene chloride. The organic layer was washed with 10% NaOH, water, brine, and dried over sodium sulfate and concentrated under vacuum to remove excess diglyme. This was purified by silica gel flush column (5% EtOAc: Hexane) and gave 18.6 g (75.9%) of yellow oil. Proton NMR and mass spectra were consistent with the product.

Step 4. 5-Phenyl-2,3-dihydrospirobenzothiepine-3,1′-cyclohexane (57)

To a mixture of 6.19 g of zinc dust and 100 ml of dry DME was added TiCl3(16.8 g, 0.108 mole). The reaction mixture was heated to reflux for 2 h. A solution of compound 56 (8.3 g, 0.023 mole) in 50 ml of DME was added dropwise to the reaction mixture in 1 h and the mixture was held at reflux for 18 h. The mixture was cooled, poured into water and extracted with ether. The organic layer was washed with water, brine, and dried over sodium sulfate, filtered through celite and concentrated under vacuum. The residue was purified by HPLC (10% EtOAc: Hexane) to give 4.6 g (64%) of white solid, mp 90-91° C. Proton and carbon NMR and mass spectra were consistent with the product.

To a solution of 57 (4.6 g, 15 mmole) in 50 ml chloroform under nitrogen was added 55% MCPBA (16.5 g, 52.6 mmole) portionwise with spatula. The reaction was held at reflux for 18 h and washed with 10% NaOH(3×), water, brine, and dried over sodium sulfate and concentrated under vacuum to give 5 g of crude product. This was recrystallized from Hexane/EtOAc to give 4.31 g (81%) of yellow solid, mp 154-155° C. Proton and carbon NMR and mass spectra were consistent with the product

A mixture of 0.5 g (1.4 mmoles) of 58, 20 ml of ethanol, 10 ml of methylene chloride and 0.4 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 3 h at room temperature. The crude reaction slurry was filtered through Celite and evaporated to dryness. The residue was purified by HPLC (10% EtOAc-Hexane, 25% EtOAc-Hexane). The first fraction was 300 mg (60%) as a white solid, mp 99-100° C. Proton NMR showed this was a trans isomer. The second fraction gave 200 mg of solid which was impure cis isomer.

To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of CH2Cl2, was added 8 g of 50% NaOH and one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst. The reaction mixture was stirred for 10 h at room temperature. Twenty g of ice was added to the mixture and the mixture was extracted with CH2Cl2 (3×10 ml) washed with water, brine and dried over MgSO4 and concentrated in vacuo to recover 0.15 g of crude product. This was recrystallized from Hexane/EtOAc to give 125 mg of white crystal, mp 209-210° C. Proton and carbon NMR and mass spectra were consistent with the product.

To a solution of 0.5 g (1.47 mmole) of compound 47 in 5 ml of anhydrous THF was added 0.17 g (1.47 mmole) of 95% potassium t-butoxide. The reaction mixture was stirred at room temperature for 18 h and quenched with 10 ml of 10% HCl. The organic was extracted into methylene chloride. The methylene chloride extract was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by HPLC (2% EtOAc-hexane) to give 47 mg of 61 in the second fraction and 38 mg of 62 in the third fraction. Proton NMR and mass spectra were consistent with the assigned structures.

An autoclave was charged with 200 mg of 37 in 40 cc ethanol and 0.02 g 10% Pd/C. After purging with nitrogen the clave was charged with 100 psi hydrogen and heated to 55° C. The reaction was monitored by TLC and mass spec and allowed to proceed until all of 37 was consumed. After the reaction was complete the catalyst was filtered and the solvent was removed in vacuo and the only observable product was amine 63. This same procedure was used to produce 64 from 38.

Alklation of e-methoxyphenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3′-methoxybenzyl)phenol in 35% yield. This material was converted to compound 65, mp 138.5-141.5° C., and compound 66, mp 115.5-117.5° C., by the procedure similar to that in Example 18 method B.

Alkylation of 4-methoxyphenol with 3-(trifluoromethyl)benzyl chloride according o the procedure described in J. Chem. Soc. 2431 (1958) gave 4-methoxy-2-(3′-trifluoromethyl)benzyl)phenol. This material was converted to compound 67, mp 226.5-228° C., and compound 68, mp 188-190° C., byu the procedure similar to that in Example 18 method B.

Alkylation of 4-methoxyphenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(4′-fluorobenzyl)phenol. This material was converted to compound 69 and compound 70 by the procedure similar to that in Example 18 method B.

Alkylation of 4-methoxyphenol with 3-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(3′-fluorobenzyl)phenol. This material was converted to compound 71 and compound 72 by the procedure similar to that in Example 18 method B.

Alkylation of 4-methoxyphenol with 2-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(2′-fluorobenzyl)phenol. This material was converted to compound 73 and compound 74 by the procedure similar to that in Example 18 method B.

Alklation of 4-bromophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-bromo-2-(3′-methoxybenzy)phenol. This material was converted to compound 75, mp 97-101.5° C., and compound 76, mp 102-106° C., by the procedure similar to that in Example 18 to method B.

Alklation of 4-fluorophenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-fluoro-2-(4′fluorobenzl)phenol. This material was converted to compound 77, mp 228-230° C., and compound 78, mp 134.5-139° C., by the procedure similar to that in Example 18 method B.

Alkylation of 4-fluorophenol with 3-methoxybenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-fluoro-2-(3′-methoxybenzyl)phenol. This material was converted to compound 79, as a solid and compound 80, mp 153-155° C., by the procedure similar to that in Example 18 method B.

A mixture of 0.68 (1.66 mmol) of compound 77, 0.2 g (5 mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at room temperature for 16 days. The reaction mixture was dilute with ether and washed with water and brine and dried over MgSO4. The ether solution was concentrated in vacuo. The residue was purified by HPLC (20% ethyl acetate in hexanes). The first fraction was impure (3α,4α,5α)3-butyl-3-ethyl-4-hydroxy-7-methylthio-5-(4′-fluorophenyl)-2,3,4,5-tetrahydrobenzothiepine-1,1-dioxide. The second fraction was compound 81, mp 185-186.5° C.

A mixture of 0.53 g (1.30 mmol) of compound 78 and 5 ml of pyrrolidine was held at reflux for 1 h. The reaction mixture was diluted with ether and washed with water and brine and dried over MgSO4. The ether solution was concentrated in vacuo. The residue was crystallized from ether-hexanes to give compound 82, mp 174.5-177° C.

A mixture of 0.4 g (0.98 mmol) of compound 78 and 5.0 g (56 mmol) of morpholine was held at reflux for 2 h and concentrated in vacuo. The residue was diluted with ether (30 ml) and washed with water and brine and dried over MgSO4.

The ether solution was concentrated in vacuo. The residue was recrystallized from ether-hexanes to give compound 83, mp 176.5-187.5° C.

Alkylation of 4-methylphenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methyl-2-(4′-fluorobenzyl)phenol). This material was converted to compound 84 and compound 85 by the procedure similar to that in Example 18 method B.

To a solution of 0.52 (1.2 mmol) of compound 66 in 20 ml of methylene chloride was added 1.7 g (6.78 mmol) of born tribromide. The reaction mixture was cooled to −78° C. and was stirred for 4 min. An additional 0.3 ml of boron tribromide was added to the reaction mixture and the reaction mixture was stirred at −78° C. for 1 h and quenced with 2 N HCl. The organic was extracted into ether. The ether layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue (0.48 g) was purified by HPLC (30% ethyl acetate in hexanes). The first fraction was 0.11 g of compound 86 as a white solid, mp 171.5-173° C. The second fraction was crystallized from chloroform to give 0.04 g of compound 87 as a white solid, mp 264° C. (dec).

A mixture of 0.20 g (0.49 mmol) of compound 78, and 2.0 g (35 mmol) of aztidine was held at reflux for 3 h and concentrated in vacuo. The residue was diluted with ether (30 ml) and washed with water and brine and dried over MgSO4. The ether solution was concentrated on a steam bath. The separated crystals were filtered to give 0.136 g of 89 as prisms, mp 196.5-199.5° C.

A mixture of 0.4 g (0.95 mmol) of compound 79, 0.08 g (1.14 mmol) of sodium methanethiolate and 15 ml of anhydrous DMF was stirred at 60° C. for 2 h. An additional 1.4 mmol of sodium methanethiolate was added to the reaction mixture and the mixture was stirred at 60° C. for an additional 2 h. The reaction mixture was triturated with 100 ml of water and extracted methylene chloride. The methylene chloride water mixture was filtered through Celite and the methylene chloride layer was dried over MgSO4 and concentrated in vacuo. The first fraction (0.1 g) was compound 90, mp 117-121° C. The second fraction (0.16 g) was compound 91, mp 68-76° C.

A 50 ml rb flash under a nitrogen atmosphere was charged with 0.54 g of M-Tres-5000 (Polyethyleneglycol Tresylate [methoxy-PEG-Tres,MW 5000] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Ala. 35801), 0.055 g Compound No. 136, 0.326 CSCO3 and 2 cc anhydrous acetonitrile. The reaction was stirred at 30° C. for 5 days and then the solution was filtered to remove salts. Next, the acetonitrile was removed under vacuum and the product was dissolved in THF and then precipitated by addition of hexane. The polymer precipitate was isolate by filtration from the solvent mixture (THF/hexane). This precipitation procedure was continued until no Compound No. 136 was detected in the precipitated product (by TLC SiO2). Next, the polymer precipitate was dissolved in water and filtered and the water soluble polymer was dialyzed for 48 hours through a cellulose dialysis tube (Spectrum® 7, 45 mm×0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried. The NMR was consistent with the desired product A and gel permeation chromatography indicated the presence of a 4500 MW polymer and also verified that no free Compound No. 136 was present. This material was active in the IBAT in vitro cell assay.

Example 51Preparation of Compound 140

Compound 140 is prepared as noted below. A 2-necked 50 ml round bottom Flask was charged with 0.42 g of Tres-3400 (Polyethyleneglycol Tresylate [Tres-PEG-Tres,MW 3400] purchased from Shearwater Polymers Inc., 2130 Memorial Parkway, SW, Huntsville, Ala. 35801), 0.1 potassium carbonate, 0.100 g of Compound No. 111 and 5 ml anhydrous DMF. Stir for 6 days at 27° C. TLC indicated the disappearance of the starting Compound No. 111. The solution was transferred to a separatory funnel and diluted with 50 cc methylene chloride and then extracted with water. The organic layer was evaporated to dryness by means of a rotary evaporator. Dry wgt. 0.4875 g. Next, the polymer was dissolved in water and then dialyzed for 48 hours at 40° C. through a cellulose dialysis tube (spectrum® 7, 45 mm×0.5 ft, cutoff 1,000 MW). The polymer solution was then removed from the dialysis tube and lyophilized until dried 0.341 g). NMR was consistent with the desired product 140.

Example 52

A 10 cc vial was charged with 0.21 g of Compound No. 136 (0.5 mmoles), 0.17 g (1.3 mmoles)potassium carbonate, 0.6 g (1.5 mmoles) of 1,2-bis-2-iodoethoxy)-ethane and 10 cc DMF. The reaction was stirred for 4 days at room temperature and then worked up by washing with ether/water. The ether layer was stripped to dryness and the desired product Compound No. 134 was isolated on a silica gel column using 80/20 hexane ethyl acetate.

Example 53

Example 54

Preparation of compound no. 112 is described below. A two necked 25 ml round bottom Flask was charged with 0.5 g (1.24 mmoles) of compound no. 134, infra, 13 mls of anhydrous DMF, 0.055 g of 60% NaH dispersion and 0.230 g (0.62 mmoles) of 1,2-Bis [2-iodoethoxylethane] at 10° C. under nitogen. Next, the reaction was slowly heated to 40° C. After 14 hours all of the Compound No. 113 was consumed and the reaction was cooled to room temperature and extracted with ether/water. The ether layer was evaporated to dryness and then chromatographed on Silicage (80/20 ethyl acetate/hexane). Isolated Compound No. 112 (0.28 g) was characterized by NMR and mass spec.

Example 55

Preparation of compound no. 135 is described below. In a 50 ml round bottom Flask, add 0.7 g (1.8 mmoles) of Compound No. 136, 0.621 g of potassium carbonate, 6 ml DMF, and 0.33 g of 1,2-Bis [2-iodoethoxylethane]. Stir at 40° C. under nitrogen for 12 hours. The workup and isolation was the same procedure for Compound No. 112.

Examples 56 and 57 (Compound Nos. 131 and 137)

The compositions of these compounds are shown in Table 3, infra.

The same procedure as for Example 55 except appropriate benzothiepine was used.

Example 58 (Compound No. 139)

The composition of this compound is shown in Table 3 infra.

Same procedure as for Example 55 with appropriate benzothiepine 1,6 diiodohexane was used instead of 1,2-Bis [2-iodoethoxylethane].

Example 59 (Compound No. 101)

This compound is prepared by condensing the 7-NH2 benzothiepine with the 1,12-dodecane dicarboxylic acid or acid halide.

Example 60 (Compound No. 104)

2-Chloro-5-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-5-nitrodiphenylmethane 32. Reaction of 32 (similar to S2-32 of Scheme 2, supra) with lithium sulfide followed by reacting the resulting sulfide with mesylate IV (similar to compound S2-33 of Scheme 2, supra) gives sulfide-aldehyde XXIII (similar to compound S2-34 of Scheme 2, supra) Oxidation of XXIII (not shown) with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme 8 below). Reduction of the sulfone-aldehyde XXIV with 100 psi hydrogen and 55° C. for 12 hours catalyzed by palladium on carbon in the same reaction vessel together with R7CHO yields the substituted dimethylamine derivative XXVIII. Cyclization of XXVIII with potassium t-butoxide yields a mixture of substituted amino derivatives XXIXc and XXIXd.

A 0.1 g (0.159 mmoles) sample of Compound No. 134 was dissolved in 15 ml of anhydrous acetonitrile in a Fischer-porter bottle and then trimethylamine was bubbled through the solution for 5 minutes at 0° C. and then capped and warmed to room temperature. The reaction was stirred overnight and the desired product was isolated by removing solvent by rotary evaporation.

Structures of the compounds of Examples 33 to 72 are shown in Tables 3 and 3A, infra.

Examples 73-79, 87, 88 and 91-102

Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, compounds were prepared having the structures set forth in Table 3, infra. The starting materials illustrated in the reaction schemes shown above were varied in accordance with principles of organic synthesis well known to the art to introduce the indicated substituents in the 4- and 5-positions (R4A, R4B, R5A, R5B) and in the indicated position on the benzo ring (R6).

Structures of the the compounds produced in Examples 73-102 are set forth in Tables 3 and 3A, infra.

After 24 hrs, the solution was poured into 300 mls 1N HCl soln. (cold). Stir this for 15 min. Extract several times with diethyl ether. Extract organic layer once with 2% aqueous NaOH then twice with water. Dry organic layer with MgSO4, dry on vac line. Solid is washed well with ether and then ethanol before drying. Wt=34.57 g (mixture of meta, ortho and para).

Elemental

Theory

found

C

57.65

57.45

H

3.46

5.51

N

4.8

4.8

Cl

12.15

12.16

With the next step of the reduction of the ketone with trifluoromethane sulfonic aid and triethyl silane, crystallization with ethyl acetate/hexane affords pure 4-chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene.

4-Chloro-3-[4-methoxy-phenylmethyl]-nitrobenzene was then reacted as specified in the synthesis of 117 and 118 from 2-chloro-4-nitrophenylmethane. From these procedures 115 and 116 can be synthesized. Compounds 111 and 113 can be synthesized from the procedure used to prepare Compound 121. See Table 3, infra.

Compound 114 can be prepared by reaction of 116 with ethyl mercaptan and aluminum trichloride.

Examples 85 and 86Preparation of 117 and 118

2-Chloro-5-nitrobenzophenone is reduced with triethylsilane and trifluoromethane sulfonic acid to 2-chloro-5-nitrodiphenylmethane 32, supra. Reaction of 32 (similar to S2-32 of Scheme 2, supra) with lithium sulfide followed by reacting the resulting sulfide with mesylate IV (similar to compound S2-33 of Scheme 2, supra) gives sulfide-aldehyde XXIII (similar to compound S2-34 of Scheme 2, supra). Oxidation of XXIII (not shown) with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV (see Scheme 8 below). Reduction of the sulfone-aldehyde XXIV with 100 psi hydrogen and 55° C. for 12 hours catalyzed by palladium on carbon in the same reaction vessel together with RCHO yields the substituted dimethylamine derivative XXVIII. Cyclization of XXVIII with potassium t-butoxide yields a mixture of substituted amino derivatives XXIXc and XXIXd. See SCHEME 8, supra.

The sulfone-aldehyde (31.8 g) was dissolved in ethanol/toluene and placed in a parr reactor with 100 ml toluene and 100 ml of ethanol and 3.2 g of 10% Pd/C and heated to 55° C. and 100 psi of hydrogen gas for 14 hours. The reaction was then filtered to remove the catalyst. The amine product (0.076 moles, 29.5 g) from this reaction was then reacted with benzyl chloroformate (27.4 g) in toluene in the presence of 35 g of potassium carbonate and stirred at room temperature overnight. After work up by extraction with water, the CBZ protected amine product was further purified by precipitation from toluene/hexane.

The CBZ protected amine product was then reacted with 3 equivalents of potassium t-butoxide in THF at 0° C. to yield compounds 117 and 118 which were separated by silica gel column chromatography.

Examples 89 and 90Preparation of 121 or 122

Compound 118 (0.013 moles, 6.79 g) is dissolved in 135 ml of dry chloroform and cooled to −78° C., next 1.85 ml of boron tribromide (4.9 g) was added and the reaction is allowed to warm to room temperature. Reaction is complete after 1.5 hours. The reaction is quenched by addition of 10% potassium carbonate at 0° C. and extract with ether. Removal of ether yields Compound No. 121. See Table 3, infra. A similar procedure can be used to produce 122 from 117. See Table 3, infra.

Examples 93-96

Compounds 126, 127, 128 and 129 as set forth in Table 3 were prepared substantially in the manner described above for compounds 115, 116, 111 and 113, respectively, except that fluorobenzene was used as a starting material in place of anisole.

TABLE 3

Specific Compounds (#102-111, 113-130, 132-134, 136, 138, 142-144,

262-296)

Cp #

R3A

R3B

R4A

R4B

R5A

R5B

(R6)m

102

Et—

n-Bu—

HO—

H—

Ph—

H—

I−, 7-(CH3)3N+—

103

n-Bu—

Et—

HO—

H—

Ph—

H—

I−7, (CH3)3N+—

104

Et—

n-Bu—

HO—

H—

Ph—

H—

7-(CH3)2N—

105

Et—

n-Bu—

HO—

H—

Ph—

H—

7-CH3SO2NH—

106

Et—

n-Bu—

HO—

H—

Ph—

H—

7-Br—CH2—CONH—

107

n-Bu—

Et—

HO—

H—

p-n-C10H21—O—Ph—

H—

7-NH2—

108

Et—

n-Bu—

HO—

H—

Ph—

H—

7-C5H11CONH—

109

Et—

n-Bu—

HO—

H—

p-n-C10H21—O—Ph—

H—

7-NH2—

110

Et—

n-Bu—

HO—

H—

Ph—

H—

7-CH3CONH—

111

n-Bu—

Et—

HO—

H—

p-HO—Ph—

H—

7-NH2—

113

Et—

n-Bu—

HO—

H—

p-HO—Ph—

H—

7-NH2—

114

Et—

n-Bu—

HO—

H—

p-CH3O—Ph—

H—

7-NH2—

115

n-Bu—

Et—

HO—

H—

p-CH3O—Ph—

H—

7-NH—CBZ

116

Et—

n-Bu—

HO—

H—

p-CH3O—Ph—

H—

7-NH—CBZ

117

n-Bu—

Et—

HO—

H—

Ph—

H—

7-NH—CBZ

118

Et—

n-Bu—

HO—

H—

Ph—

H—

7-NH—CBZ

119

Et—

n-Bu—

HO—

H—

Ph—

H—

7-NHCO2-t-Bu

120

n-Bu—

Et—

HO—

H—

Ph—

H—

7-NHCO2-t-Bu

121

Et—

n-Bu—

HO—

H—

Ph—

H—

7-NH2—

122

n-Bu—

Et—

HO—

H—

Ph—

H—

7-NH2—

123

Et—

n-Bu—

HO—

H—

Ph—

H—

7-n-C6H13—NH—

124

n-Bu—

Et—

HO—

H—

Ph—

H—

7-n-C6H13—NH—

125

Et—

n-Bu—

HO—

H—

Ph—

H—

I−, 8-(CH3)3)N+(CH2CH2O)3—

126

n-Bu—

Et—

HO—

H—

p-F—Ph—

H—

7-NH—CBZ

127

n-Bu—

Et—

HO—

H—

p-F—Ph—

H—

7-NH2—

128

Et—

n-Bu—

HO—

H—

p-F—Ph—

H—

7-NH—CBZ

129

Et—

n-Bu—

HO—

H—

p-F—Ph—

H—

7-NH2—

130

Et—

n-Bu—

HO—

H—

Ph—

H—

I−, 8-(CH3)3N+C6H12O—

132

Et—

n-Bu—

HO—

H—

Ph—

H—

8-phthalimidyl-C6H12O—

133

Et—

n-Bu—

HO—

H—

Ph—

H—

8-n-C10H21—

134

Et—

n-Bu—

HO—

H—

Ph—

H—

8-I-(C2H4O)3—

136

Et—

n-Bu—

HO—

H—

Ph—

H—

8-HO—

138

n-Bu—

Et—

HO—

H—

Ph—

H—

8-CH3CO2—

142

Et—

n-Bu—

H—

HO—

H—

m-CH3O—Ph—

7-CH3S—

143

Et—

n-Bu—

HO—

H—

m-CH3O—Ph

H—

7-CH3S—

144

Et—

n-Bu—

HO—

H—

p-F—Ph—

H—

7-(N)-azetidine

262

Et—

n-Bu—

HO—

H—

m-CH3O—Ph—

H—

7-CH3O—

263

Et—

n-Bu—

H—

HO—

H—

m-CH3O—Ph—

7-CH3O—

264

Et—

n-Bu—

HO—

H—

m-CF3—Ph—

H—

7-CH3O—

265

Et—

n-Bu—

H—

HO—

H—

m-CF3—Ph—

7-CH3O—

266

Et—

n-Bu—

HO—

H—

m-HO—Ph—

H—

7-HO—

267

Et—

n-Bu—

HO—

H—

m-HO—Ph—

H—

7-CH3O—

268

Et—

n-Bu—

HO—

H—

p-F—Ph—

H—

7-CH3O—

269

Et—

n-Bu—

H—

HO—

H—

p-F—Ph—

7-CH3O—

270

Et—

n-Bu—

HO—

H—

p-F—Ph—

H—

7-HO—

271

Et—

n-Bu—

HO—

H—

m-CH3O—Ph—

H—

7-Br—

272

Et—

n-Bu—

H—

HO—

H—

m-CH3O—Ph—

7-Br—

273

Et—

n-Bu—

H—

HO—

H—

p-F—Ph—

7-F—

274

Et—

n-Bu—

HO—

H—

p-F—Ph—

H—

7-F—

275

Et—

n-Bu—

H—

HO—

H—

m-CH3O—Ph—

7-F—

276

Et—

n-Bu—

HO—

H—

m-CH3O—Ph

H—

7-F—

277

Et—

n-Bu—

HO—

H—

m-F—Ph—

H—

7-CH3O—

278

Et—

n-Bu—

H—

HO—

H—

o-F—Ph—

7-CH3O—

279

Et—

n-Bu—

H—

HO—

H—

m-F—Ph—

7-CH3O—

280

Et—

n-Bu—

HO—

H—

o-F—Ph—

H—

7-CH3O—

281

Et—

n-Bu—

HO—

H—

p-F—Ph—

H—

7-CH3S—

282

Et—

n-Bu—

HO—

H—

p-F—Ph—

H—

7-CH3—

283

Et—

n-Bu—

H—

HO—

H—

p-F—Ph—

7-CH3—

284

Et—

n-Bu—

HO—

H—

p-F—Ph—

H—

7-(N)-morpholine

285

Et—

n-Bu—

HO—

H—

p-F—Ph—

H—

7-(N)-pyrrolidine

286

Et—

Et—

HO—

H—

Ph—

H—

7-NH—CBZ—

287

Et—

Et—

HO—

H—

Ph—

H—

7-NH2—

288

CH3—

CH3—

HO—

H—

Ph—

H—

7-NH2—

289

n-C3H7—

n-C3H7—

HO—

H—

Ph—

H—

7-NH2—

290

n-Bu—

n-Bu—

HO—

H—

Ph—

H—

7-NH2—

291

n-Bu—

n-Bu—

HO—

H—

Ph—

H—

7-NH—CBZ—

292

n-Bu—

n-Bu—

HO—

H—

p-F—Ph—

H—

7-NH2—

293

n-Bu—

n-Bu—

HO—

H—

Ph—

H—

7-PhCH2N—

294

n-Bu—

n-Bu—

HO—

H—

Ph—

H—

7-(CH3)2N—

295

Et—

n-Bu—

HO—

H—

p-I—(C2H4O)3—Ph—

H—

7-NH2—

296

Et—

n-Bu—

HO—

H—

I−, p-(CH3)3N+(C2H4O)3—Ph—

H—

7-NH2—

TABLE 3A

Bridged Benzothiepines (#101, 112, 131, 135, 137, 139-141)

CPD #101 (Example 59)

CPD #112 (Example 53)

CPD #131 (Example 56)

CPD #135 (Example 55)

CPD #137 (Example 57)

CPD #139 (Example 58)

PEG = 3400 molecular weight polyethyleneglycol bridge

CPD #140 (Example 51)

CPD #141 (Example 50)

Examples 104-231

Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 4 below. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5-positions (R3A, R3B, R4A, R5A) and in the indicated position on the benzo ring (R6). See Table 4 below.

TABLE 4

Alternative compounds #1 (#302-312, 314-430)

Cpd #

R5A

(R6)m

302

p-F—Ph—

7-(1-aziridine)

303

p-F—Ph—

7-EtS—

304

p-F—Ph—

7-CH3S(O)—

305

p-F—Ph—

7-CH3S(O)2—

306

p-F—Ph—

7-PhS—

307

p-F—Ph—

7-CH3S—

9-CH3S—

308

p-F—Ph—

7-CH3O—

9-CH3O—

309

p-F—Ph—

7-Et—

310

p-F—Ph—

7-iPr—

311

p-F—Ph—

7-t-Bu—

312

p-F—Ph—

7-(1-pyrazole)-

314

m-CH3O—Ph

7-(1-azetidine)

315

m-CH3O—Ph—

7-(1-aziridine)

316

m-CH3O—Ph—

7-EtS—

317

m-CH3O—Ph—

7-CH3S(O)—

318

m-CH3O—Ph—

7-CH3S(O)2—

319

m-CH3O—Ph—

7-PhS—

320

m-CH3O—Ph

7-CH3S—

9-CH3S—

321

m-CH3O—Ph

7-CH3O—

9-CH3O—

322

m-CH3O—Ph

7-Et—

323

m-CH3O—Ph

7-iPr—

324

m-CH3O—Ph

7-t-Bu—

325

p-F—Ph—

6-CH3O—

7-CH3O—

8-CH3O—

326

p-F—Ph—

7-(1-azetidine)

9-CH3—

327

p-F—Ph—

7-EtS—

9-CH3—

328

p-F—Ph—

7-CH3S(O)—

9-CH3—

329

p-F—Ph—

7-CH3S(O)2—

9-CH3—

330

p-F—Ph—

7-PhS—

9-CH3—

331

p-F—Ph—

7-CH3S—

9-CH3—

332

p-F—Ph—

7-CH3O—

9-CH3—

333

p-F—Ph—

7-CH3—

9-CH3—

334

p-F—Ph—

7-CH3O—

9-CH3O—

335

p-F—Ph—

7-(1-pyrrole)

336

p-F—Ph—

7-(N)N′-methylpiperazine

337

p-F—Ph—

Ph—

338

p-F—Ph—

7-CH3C(═CH2)—

339

p-F—Ph—

7-cyclpropyl

340

p-F—Ph—

7-(CH3)2NHN—

341

p-F—Ph—

7-(N)-azetidine

9-CH3S—

342

p-F—Ph—

7-(N-pyrrolidine)

9-CH3S—

343

p-F—Ph—

7-(CH3)2N—

9-CH3S—

344

m-CH3O—Ph—

7-(1-pyrazole)

345

m-CH3O—Ph—

7-(N)N′-methylpiperazine

346

m-CH3O—Ph—

Ph—

347

m-CH3O—Ph—

7-CH3C(═CH2)—

348

m-CH3O—Ph—

7-cyclopropyl

349

m-CH3O—Ph—

7-(CH3)2NHN—

350

m-CH3O—Ph—

7-(N)-azetidine

9-CH3S—

351

m-CH3O—Ph—

7-(N-pyrrolidine)-

9-CH3S—

352

m-CH3O—Ph—

7-(CH3)2N—

9-CH3S—

353

m-CH3O—Ph—

6-CH3O—

7-CH3O—

8-CH3O—

354

m-CH3O—Ph—

7-(1-azetidine)

9-CH3—

355

m-CH3O—Ph—

7-EtS—

9-CH3—

356

m-CH3O—Ph—

7-CH3S(O)—

9-CH3—

357

m-CH3O—Ph—

7-CH3S(O)2—

9-CH3—

358

m-CH3O—Ph—

7-PhS—

9-CH3—

359

m-CH3O—Ph—

7-CH3S—

9-CH3—

360

m-CH3O—Ph—

7-CH3O—

9-CH3—

361

m-CH3O—Ph—

7-CH3—

9-CH3—

362

m-CH3O—Ph—

7-CH3O—

9-CH3O—

363

thien-2-yl

7-(1-aziridine)

364

thien-2-yl

7-EtS—

365

thien-2-yl

7-CH3S(O)—

366

thien-2-yl

7-CH3S(O)2—

367

thien-2-yl

7-PhS—

368

thien-2-yl

7-CH3S—

9-CH3S—

369

thien-2-yl

7-CH3O—

9-CH3O—

370

thien-2-yl

7-Et—

371

thien-2-yl

7-iPr—

372

thien-2-yl

7-t-Bu—

373

thien-2-yl

7-(1-pyrrole)-

374

thien-2-yl

7-CH3O—

375

thien-2-yl

7-CH3S—

376

thien-2-yl

7-(1-azetidine)

377

thien-2-yl

7-Me—

378

5-Cl-thien-2-yl

7-(1-azetidine)

379

5-Cl-thien-2-yl

7-(1-aziridine)

380

5-Cl-thien-2-yl

7-EtS—

381

5-Cl-thien-2-yl

7-CH3S(O)—

382

5-Cl-thien-2-yl

7-CH3S(O)2—

383

5-Cl-thien-2-yl

7-PhS—

384

5-Cl-thien-2-yl

7-CH3S—

9-CH3S—

385

5-Cl-thien-2-yl

7-CH3O—

9-CH3O—

386

5-Cl-thien-2-yl

7-Et—

387

5-Cl-thien-2-yl

7-iPr—

388

5-Cl-thien-2-yl

7-t-Bu—

389

5-Cl-thien-2-yl

7-CH3O—

390

5-Cl-thien-2-yl

7-CH3S—

391

5-Cl-thien-2-yl

7-Me

392

thien-2-yl

7-(1-azetidine)

9-CH3—

393

thien-2-yl

7-EtS—

9-CH3—

394

thien-2-yl

7-CH3S(O)—

9-CH3—

395

thien-2-yl

7-CH3S(O)2—

9-CH3—

396

thien-2-yl

7-PhS—

9-CH3—

397

thien-2-yl

7-CH3S—

9-CH3—

398

thien-2-yl

7-CH3O—

9-CH3—

399

thien-2-yl

7-CH3—

9-CH3—

400

thien-2-yl

7-CH3O—

9-CH3O—

401

thien-2-yl

7-(1-pyrazrole)

402

thien-2-yl

7-(N)N′-methylpiperazine

403

thien-2-yl

Ph—

404

thien-2-yl

7-CH3C(═CH2)—

405

thien-2-yl

7-cyclpropyl

406

thien-2-yl

7-(CH3)2NHN—

407

thien-2-yl

7-(N)-azetidine

9-CH3S—

408

thien-2-yl

7-(N-pyrrolidine)

9-CH3S—

409

thien-2-yl

7-(CH3)2N—

9-CH3S—

411

5-Cl-thien-2-yl

7-(1-pyrazrole)

412

5-Cl-thien-2-yl

7-(N)N′-methylpiperazine

413

5-Cl-thien-2-yl

Ph—

414

5-Cl-thien-2-yl

7-CH3C(═CH2)—

415

5-Cl-thien-2-yl

7-cyclopropyl

416

5-Cl-thien-2-yl

7-(CH3)2NHN—

417

5-Cl-thien-2-yl

7-(N)-azetidine

9-CH3S—

418

5-Cl-thien-2-yl

7-(N-pyrrolidine)-

9-CH3S—

419

5-Cl-thien-2-yl

7-(CH3)2N—

9-CH3S—

420

5-Cl-thien-2-yl

7-(1-azetidine)

9-CH3—

421

5-Cl-thien-2-yl

7-EtS—

9-CH3—

422

5-Cl-thien-2-yl

7-CH3S(O)—

9-CH3—

423

5-Cl-thien-2-yl

7-CH3S(O)2—

9-CH3—

424

5-Cl-thien-2-yl

7-PhS—

9-CH3—

425

5-Cl-thien-2-yl

7-CH3S—

9-CH3—

426

5-Cl-thien-2-yl

7-CH3O—

9-CH3—

427

5-Cl-thien-2-yl

7-CH3—

9-CH3—

428

5-Cl-thien-2-yl

7-CH3O—

9-CH3O—

429

thien-2-yl

6-CH3O—

7-CH3O—

8-CH3O—

430

5-Cl-thien-2-yl

6-CH3O—

7-CH3O—

8-CH3O—

Examples 232-1394

Using in each instance a method generally described in those of Examples 1 to 72 appropriate to the substituents to be introduced, including where necessary other common synthesis expedients well known to the art, compounds are prepared having the structures set forth in Table 5-7 below. The starting materials illustrated in the reaction schemes shown above are varied in accordance with principles of organic synthesis well known to the art in order to introduce the indicated substituents in the 4- and 5-positions (R3A, R3B, R4A, R5A) and in the indicated position on the benzo ring (R6).